JP2009511592A - New heterocyclic compounds - Google Patents

Abstract

  The present invention relates to novel compounds that are opioid receptor antagonists or inverse agonists. Such compounds are useful for treating obesity and related diseases and / or symptoms in mammals, particularly humans. Also disclosed are methods of making and utilizing such compounds.

Description

The present invention relates to novel heterocyclic compounds that are antagonists or inverse agonists of one or more opioid receptors, pharmaceutical compositions containing them, methods for preparing them, and their use in therapy.

BACKGROUND OF THE INVENTION Obesity is a medical condition that is prevalent among humans in countries around the world. Obesity is associated with other diseases or conditions that disrupt life and lifestyle. Obesity is recognized as a serious risk factor for other diseases and / or symptoms such as diabetes, hypertension, and arteriosclerosis. It is also known that weight gain due to obesity can stress joints such as the knee joint and cause arthritis, pain, and stiffness.

  Overeating and obesity can cause such problems, so many people are interested in losing weight and / or maintaining a healthy weight.

  Opioid receptor antagonists or inverse agonists have been shown to reduce body weight in obese rats. In addition, the ability to bind to opioid receptors and exhibit antagonistic activity is associated with many other diseases or conditions not related to obesity, such as drug and / or substance addiction, depression, opiate overdose, irritable bowel syndrome, sepsis It has been suggested to be useful in the treatment of sexual shock, nausea, vomiting, and stroke. Therefore, there is a growing need for new opioid antagonists for treating obesity, diseases and / or symptoms associated with obesity, and the diseases and / or symptoms associated with obesity described above.

SUMMARY OF THE INVENTION The present invention provides a compound of formula 1:

[Wherein R ¹ is hydrogen, C _1-12 alkyl, C _3-10 cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl, heteroarylalkyl, cycloalkenyl, C _2-12 fluoroalkyl, C _3-10 alkoxy And selected from the group consisting of heteroalkyl;
R ² consists of C _3-12 alkyl, C _3-10 cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl, heteroarylalkyl, cycloalkenyl, C _3-12 fluoroalkyl, C _3-10 alkoxy, and heteroalkyl Selected from the group;
R ¹ and R ² may be optionally joined to form a ring;
A is selected from the group consisting of C _1-3 alkylene, and C _2-3 alkoxy bonded to the diaryl ether linker (the diaryl ether linker is shown as “—O—” in Formula 1) in the meta or para position. Selected;
R ³ and R ⁴ are each independently of the group consisting of —H, —F, —Cl, —Br, —OH, —OC _1-3 alkyl, —C _1-3 fluoroalkyl and —C _1-3 alkyl. Selected;
X, Y, and Z are each independently selected from the group consisting of —N, —NH, —CH, —O, —S, —NR ⁵ , and —CR ⁶ , where R ⁵ and R ⁶ are Each independently is C _1-6 alkyl or fluoroalkyl]
And pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.

In preferred embodiments, the carbon atom (of R ¹ and R ² ) that is attached to the nitrogen is not aromatic or carbonyl.

In one embodiment, A is methylene bonded in the para position to the diaryl ether linker; R ¹ is hydrogen; R ² is arylethyl, arylmethyl, C _4-10 alkyl, cycloalkenyl, cycloalkyl, Selected from the group consisting of heterocyclylmethyl and heterocyclylethyl; R ³ and R ⁴ are each independently selected from the group consisting of —H and —F; either X or Z is —NH and the others are —CH Or -N; and Y is -CH or -N.

  A pharmaceutical composition comprising (i) a compound of formula 1, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and (ii) at least one carrier (excipient or diluent) Also referred to as), preferably a pharmaceutical composition comprising a pharmaceutically acceptable carrier is provided.

  Further, a method of treatment (including prophylaxis) comprising (i) a compound of formula 1, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof and (ii) at least one carrier. There is provided a method as described above comprising administering to a mammal, especially a human, a pharmaceutical composition comprising (an excipient or diluent). Also a method of treatment (including prophylaxis) comprising administering a compound of formula 1, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof to a mammal, especially a human. Said method is provided.

  One aspect of the present invention includes a compound of the present invention (or salt, solvate, or functional derivative thereof) for use as an active therapeutic agent.

  Another aspect of the present invention is the use of Formula 1 for the treatment (including prophylaxis) of obesity, diabetes, hypertension, depression (major and / or bipolar), anxiety, drug addiction, and / or substance addiction. (Or a salt, solvate, or functional derivative thereof). Of these symptoms / disorders, obesity is one of the preferred treatments.

  Yet another aspect of the present invention includes the manufacture of a medicament for treating (including prophylaxis) obesity, diabetes, hypertension, depression (major and / or bipolar), anxiety, drug addiction, and / or substance addiction. In the use of a compound of formula 1 (or a salt, solvate or functional derivative thereof). Of these symptoms / disorders, obesity is one of the preferred treatments.

Detailed description terms of the invention are used in their accepted meanings. The following definitions are made clear and do not limit the defined terms.

  As used herein, a “compound of the invention” or “compound of formula 1” refers to a compound of formula 1 or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof (eg, pro Drag).

  The term “alkyl” as used herein preferably has from 1 to 12 carbon atoms and may be optionally substituted with the substitution multiplicity included in the present invention. Means hydrocarbon. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, isopentyl, n-pentyl, and the like, and substituted variants thereof Is mentioned.

As used throughout this specification, a preferred number of atoms, such as carbon atoms, is represented, for example, by the expression “C _xy alkyl,” which is defined herein to contain a defined number of carbon atoms. An alkyl group is meant. Similar terminology usage may apply to other preferred terms and ranges.

  The term “alkenyl” as used herein is a straight or branched chain containing one or more carbon-to-carbon double bonds, optionally substituted with the multiplicity of substitution included in the present invention. Means a chain aliphatic hydrocarbon. Examples include, but are not limited to, vinyl, allyl, and the like, as well as substituted variants thereof.

  The term “alkynyl” as used herein refers to a straight or branched chain containing one or more carbon-to-carbon triple bonds that may be optionally substituted with the multiplicity of substitution included in the present invention. Means an aliphatic hydrocarbon. Examples include, but are not limited to, ethynyl and the like, as well as substituted variants thereof.

  The term “alkylene” as used herein means a straight or branched divalent hydrocarbon group, preferably having from 1 to 10 carbon atoms. The alkylene groups defined herein may be optionally substituted with the multiplicity of substitution included in the present invention. Examples of “alkylene” for use in the present invention include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like, as well as substituted variants thereof.

  The term “alkenylene” as used herein is preferably a straight or branched divalent having 1 to 10 carbon atoms and containing one or more carbon-to-carbon double bonds. It means a hydrocarbon group and may be optionally substituted with the substitution multiplicity included in the present invention. Examples of “alkenylene” for use in the present invention include, but are not limited to, vinylene, arylene, 2-propenylene, and the like, as well as substituted variants thereof.

  The term “alkynylene” as used herein is a straight or branched divalent carbonization, preferably having from 1 to 10 carbon atoms and containing one or more carbon-to-carbon triple bonds. This means a hydrogen group, which may be optionally substituted with the substitution multiplicity included in the present invention. Examples include, but are not limited to, ethynylene and the like, as well as substituted variants thereof.

  As used herein, the term “cycloalkyl” is optionally substituted with the multiplicity of substitutions included in the present invention, and optionally includes an alkylene linker, through which the cycloalkyl can be attached. A non-aromatic cyclic hydrocarbon ring is meant. Examples of “cycloalkyl” include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, as well as substituted variants thereof. As used herein, the term “cycloalkyl” refers to an optionally substituted ring-fused polycyclic hydrocarbon saturated and aromatic ring system, ie, a polycyclic hydrocarbon that is less than the maximum number of non-cumulative double bonds. A group such as, for example, indane, formed by ring condensation of a saturated hydrocarbon ring (such as a cyclopentyl ring) with an aromatic ring ("aryl" in this specification, such as a benzene ring).

  The term “cycloalkenyl” as used herein is optionally substituted with the multiplicity of substitutions included in the present invention, and optionally includes an alkylene linker through which the cycloalkenyl can be attached. By non-aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds. Examples of “cycloalkenyl” groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like, as well as substituted variants thereof.

  The term “cycloalkylene” as used herein refers to a divalent non-aromatic cyclic hydrocarbon ring optionally substituted with a multiplicity of substitution included in the present invention. Examples of “cycloalkylene” include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like, as well as substituted variants thereof.

  The term “cycloalkenylene” as used herein is a divalent non-aromatic containing one or more carbon-to-carbon double bonds, optionally substituted with the multiplicity of substitution included in the present invention. A cyclic hydrocarbon ring is meant. Examples of “cycloalkenylene” groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, cycloheptenylene, and the like, as well as substituted variants thereof.

  As used herein, the term “heterocycle” or “heterocyclyl” is an optionally substituted monocyclic or polycyclic optionally containing one or more degrees of unsaturation and also containing one or more heteroatoms. Means ring system. Preferred heteroatoms are N, O, and / or S, including N-oxides, S-oxides, and dioxides. Preferably, the ring is a 3-12 membered ring and is all saturated or has one or more degrees of unsaturation. Multiplicity substitutions are included within the definition of the invention. Such a ring may optionally be fused with one or more other “heterocycles” or “cycloalkyl rings”. Examples of “heterocycle” include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran, and tetrahydrothiophene.

  “Heterocyclylalkyl” as used herein, means a heterocycle, as defined herein, appended to an alkyl group, as defined herein.

  “Arylalkyl” as used herein, means an aryl group, as de? Ned herein, appended to an alkyl group, as de? Ned herein.

  As used herein, “heteroalkyl” refers to an alkyl group, as defined herein, wherein one or more atoms of the alkyl group is a heteroatom. Preferred heteroatoms are N, O, and / or S, including N-oxides, S-oxides, and dioxides.

  The term “aryl” as used herein refers to an optionally substituted benzene ring or an optionally substituted ring-fused benzene ring system, such as an anthracene, phenanthrene, or naphthalene ring system. Multiplicity substitutions are included within the scope of this definition. Examples of “aryl” groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, and the like, as well as substituted derivatives thereof.

  As used herein, the term “heteroaryl”, an optionally substituted monocyclic 5-7 membered aromatic ring, or a fused bicyclic aromatic ring comprising two of such optionally substituted aromatic rings Means system. These heteroaryl rings contain one or more heteroatoms such as nitrogen, sulfur, and / or oxygen atoms, where N-oxides, S-oxides, and dioxides are acceptable heteroatom substitutions. . Multiplicity substitutions are included within the definition of the invention. Examples of “heteroaryl” groups as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, Isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, and the like, and substituted Mutants are mentioned.

  The term “heteroarylalkyl” as used herein, means a heteroaryl, as defined herein, appended to an alkyl group, as defined herein.

  The term “halogen” as used herein means fluorine (or fluoro), chlorine (or chloro), bromine (or bromo), or iodine (or iodo). Preferably, when present, each halogen is individually fluorine or chlorine.

  The term “fluoroalkyl” as used herein, means an alkyl group, as defined herein, substituted with at least one fluorine atom. Examples of branched or straight chain “fluoroalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n, independently substituted with one or more fluorines. -Butyl, and t-butyl. The term “fluoroalkyl” should be construed to include substituents such as perfluoroalkyl groups.

The term “alkoxy” as used herein refers to the group —OR ^a , where R ^a is alkyl as defined above.

As used herein, the term “alkoxycarbonyl” has the formula:

[Wherein R ^a represents an alkyl group as defined herein].

As used herein, the term “aryloxycarbonyl” has the formula:

[Wherein Ay represents an aryl group as defined herein].

The term “heteroaryloxycarbonyl” as used herein has the formula:

[Wherein Het represents a heteroaryl group as defined herein].

The term “nitro” as used herein, means a —NO ₂ group.

  The term “cyano” as used herein, means a —CN group.

The term “azido” as used herein, means a —N ₃ group.

The term “acyl” as used herein, means an R ^b C (O) — group, wherein R ^b is each alkyl, aryl, heteroaryl, or heterocyclyl as defined herein.

  The term “oxo” as used herein, means a ═O group.

  The term “member” (and variations thereof, eg, “member”) in the context of heterocycles, heteroaryls, heteroaromatics, aryls, and aromatic groups is all atoms, carbons and heteroatoms that form the ring (Eg, N, O, and S). Thus, an example of a 6-membered heterocycle is piperidine; an example of a 6-membered heteroaryl is pyridine; and an example of a 6-membered aryl ring is benzene.

  The term “optionally” as used herein is meant to include both events that may or may not occur, and events that occur and do not occur.

Also, as used herein throughout the specification, the expression “optionally substituted” or variations thereof indicates optional substitution, including multiplicity of substitution with one or more substituents. The expression should not be construed as an overlap of the substitutions described and shown herein. Examples of optional substituents include
Alkyl; alkenyl; alkynyl; alkylsulfonyl; alkoxy; alkoxycarbonyl; cyano; halogen; haloalkyl; hydroxy; nitro; aryl (which is further acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, Heteroaryl (which may be further substituted with acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro); Arylsulfonyl (which is further acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy Or optionally substituted by nitro); heteroarylsulfonyl (which may be further substituted by acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro); Aryloxy (which may be further substituted by acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro); heteroaryloxy (which is further acyl, alkoxy, alkyl Optionally substituted by alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; , Alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro may be substituted; heteroaryloxycarbonyl (which may be further acyl, alkoxy, alkyl, alkenyl, alkynyl, alkyl) Optionally substituted by sulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro); or —N (R ^* ) _{2 wherein} , for each occurrence, R * is independently hydrogen, alkyl, alkenyl, Selected from alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, where each such occurrence appears Or heteroaryl 1 or more acyl, alkoxy, alkyl, alkenyl, alkylsulfonyl, forming cyano, halogen, haloalkyl, hydroxy, or may be substituted by nitro, or two R ^* are linked a ring, then The ring optionally has additional heteroatoms (eg, N, O, S, etc.), optionally has one or more degrees of unsaturation, and optionally further acyl, alkoxy, alkyl, alkenyl, alkynyl, alkylsulfonyl , Optionally substituted by cyano, halogen, haloalkyl, hydroxy, or nitro].

  A compound of formula 1 can crystallize in more than one form, a property known as polymorphism, and such polymorphic forms (“polymorphs”) are within the scope of formula 1. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphs can also arise from deformations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubility and melting point.

  Certain compounds of Formula 1 may exist in stereoisomeric forms (eg, they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The present invention also encompasses the individual isomers of the compounds represented by Formula 1, as well as mixtures with isomers thereof in which one or more chiral centers are inverted. Certain compounds of Formula 1 can also be prepared as regioisomers. The invention includes both mixtures of regioisomers as well as individual compounds. Similarly, compounds of formula 1 may exist in tautomeric forms other than those shown in the above formulas and are intended to be included within the scope of the present invention. The present invention should be construed to include all combinations and subsets of the specific groups defined herein above. The scope of the present invention includes stereoisomers as well as purified enantiomers or enriched mixtures of enantiomers / diastereomers. Also included within the scope of the invention are the individual isomers of the compounds represented by Formula 1, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formula above as well as mixtures with isomers thereof in which one or more chiral centers are inverted.

  Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention can include acid addition salts. In general, salts are formed from pharmaceutically acceptable inorganic and organic acids, or bases, and quaternary ammonium salts. More specific examples of suitable acid salts include maleic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, humic acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid. , Lactic acid, array acid, tartaric acid, citric acid, palmonic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid (mesylate), naphthalene-2- Examples thereof include salts of sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, teronic acid, tannic acid, and the like.

  Other representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, hydrogen tartrate, borate, calcium edetate, cansylate, carbonate, clavulan Acid salt, citrate salt, dihydrochloride salt, edicyl salt salt, estolate, esylate salt, fumarate salt, glucoceptor salt, gluconate salt, glutamate salt, glycolylarsanylate salt, hexyl resorcinate salt, hydrabamine salt, hydrobromide salt , Hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl sulfate, monopotassium maleate , Mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate , Phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, basic acetate, succinate, sulfate, tannate, tartrate, theocrate, tosylate, Examples include trithiozide, trimethylammonium and valerate.

  Other pharmaceutically unacceptable salts may also be useful in the preparation of the compounds of the invention and should be considered as forming a further aspect of the invention. Although these salts, such as succinic acid, are not pharmaceutically acceptable per se, they may be useful in the preparation of salts that serve as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts.

  More specific examples of suitable basic salts include sodium, lithium, potassium, magnesium aluminum, calcium, zinc, N, N'-dibenzylethylenediamine, chloroprocaine, chlorine, diethanolamine, ethylenediamine, n-methylglucamine And procaine salts.

  As used herein, the term “solvate” refers to a variable stoichiometry formed by a solute (in this invention, a compound of Formula 1, or a salt or physiologically functional derivative thereof) and a solvent. Meaning compound. Such solvents for the purposes of the present invention should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include but are not limited to water, methanol, ethanol and acetic acid. The solvent used is preferably a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Most preferably, the solvent used is water.

The term “physiologically functional derivative” as used herein is a book that can provide (directly or indirectly) a compound of the invention or an active metabolite thereof upon administration to a mammal. It means any pharmaceutically acceptable derivative of a compound of the invention. Such derivatives (eg esters and amides) will be apparent to those skilled in the art without undue experimentation. Burger's Medicinal incorporated by reference herein to the extent that it teaches physiologically functional derivatives ^{Chemistry And Drug Discovery, 5 th Edition} , Vol 1: reference may be made to the teachings of the Principles and Practice.

Methods for preparing pharmaceutically acceptable salts, solvates, and physiologically functional derivatives of the compounds of Formula 1 are conventional in the art. For example, Burger's Medicinal Chemistry And Drug Discovery , 5 th Edition, Volume 1: see Principles and Practice.

  As used herein, the term “effective amount” means the amount of a drug or medicament that elicits a biological or medical response in a tissue, system, animal or human that is being pursued, for example, by a researcher or clinician To do. The term “therapeutically effective amount” refers to the treatment, cure, prevention or improvement of a disease, disorder or side effect, or the progression rate of a disease or disorder is reduced compared to a corresponding subject who has not received such an amount. Means any amount that yields The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of the compounds of Formula 1 and salts, solvates and physiologically functional derivatives thereof may be administered as raw chemicals. Furthermore, the active ingredient may be provided as a pharmaceutical composition.

  As used herein, the term “treatment” includes prophylaxis, alleviating a specific symptom, eliminating or reducing one or more syndromes of the symptom in a patient or subject who has previously suffered or diagnosed, Includes slowing or disappearing or reducing symptoms, as well as preventing or delaying symptoms.

  Accordingly, the present invention further comprises an effective amount of a compound of Formula 1 and salts, solvates and physiologically functional derivatives thereof and one or more pharmaceutically acceptable excipients (carriers and / or diluents). And a pharmaceutical composition (also referred to as a “pharmaceutical formulation”). The compounds of formula 1, their salts, solvates and physiologically functional derivatives are as described herein. The carrier, diluent or excipient must be acceptable in the sense of being compatible with the other ingredients of the formulation and not injurious to the recipient of the pharmaceutical composition.

  According to another aspect of the present invention, the compound of formula 1 or a salt, solvate and physiologically functional derivative thereof are mixed with one or more pharmaceutically acceptable carriers, diluents or excipients. There is also provided a process for producing a pharmaceutical formulation comprising

  The therapeutically effective amount of the compounds of the invention will depend on a number of factors. For example, the species, age and weight of the recipient, the exact symptoms and their severity requiring treatment, the nature of the formulation and the route of administration are all factors to be considered. The therapeutically effective amount shall be at the discretion of the attending physician or veterinarian. Nevertheless, an effective amount of a compound of Formula 1 for the treatment of a weakly constitutive human should generally be in the range of 0.1-100 mg / kg of recipient (mammal) body weight. More generally, an effective amount should be in the range of 1-10 mg / kg body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day will usually be 70-700 mg. This amount is given in a single dose per day, or in many (two, three, four, five or more) divided doses per day so that the total daily dose is the same Also good. The effective amount of the salt, solvate or physiologically functional derivative can be determined as a proportion of the effective amount of the compound of Formula 1 itself. Similar doses may be appropriate for the treatment of other conditions referred to herein.

  The pharmaceutical formulation may be provided in a single dosage form containing a predetermined amount of active ingredient per single dose. Such units may include, by way of non-limiting example, 0.5 mg to 1 g of a compound of formula 1 depending on the condition being treated, the route of administration, and the age, weight and condition of the patient. Preferred single dose formulations are those containing a daily or divided dose of an active ingredient as detailed hereinbefore or an appropriate fraction thereof. Such pharmaceutical preparations can be prepared by any method well known in the pharmaceutical arts.

  The pharmaceutical formulation can be by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (subcutaneous, It may be adapted for administration by intramuscular, intravenous or intradermal) routes. Such formulations may be prepared by any method known in the pharmaceutical arts, for example by combining the active ingredient with a carrier or excipient. In the present invention, the oral route is preferred.

  Pharmaceutical formulations adapted for oral administration are in individual units (capsules or tablets; powders or granules; solutions or suspensions containing aqueous or non-aqueous liquids, respectively; edible foams or whips; or oil-in-water emulsions or Water-in-oil emulsions, etc.). For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol and water. Generally, powders are prepared by grinding the compound to a suitable fine size and mixing with a suitable pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. It may also contain flavorings, preservatives, dispersants and colorants.

  Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other suitable shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the mixture before encapsulation. Disintegrating or solubilizing agents such as agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. In addition, if desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars (such as glucose or β-lactose), corn syrup, natural and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, etc. Is mentioned. Lubricants effective in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate and sodium chloride. Examples of the disintegrant include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

  Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture may be prepared by mixing the above comminuted compound with a diluent or base as described above. Optional ingredients include binders (such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone), dissolution inhibitors (such as paraffin), resorption enhancers (such as quaternary salts) and / or absorbents (bentonite, kaolin) Or dicalcium phosphate). The powder mixture can be wet granulated with a binder (such as syrup, starch paste, gum arabic mucus or a solution of cellulose or polymeric material) and passed through a sieve. As an alternative to granulation, the powder mixture can be passed through a tablet machine and the result is an imperfectly formed slug that is ground into granules. The granules can be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the tablet mold. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A transparent or opaque protective coating consisting of a shellac sealing coat, a sugar or polymeric material coating, and a wax abrasive coating may be applied. Dyestuffs may be added to these coatings to distinguish different single doses.

  Oral solutions such as solvents, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions are generally formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers (such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers), preservatives; flavoring additives (such as bran oil or natural sweeteners), saccharin or other artificial sweeteners may also be added it can.

  Where appropriate, single dose formulations for oral administration can be microencapsulated. The formulation can also be prepared by coating or embedding the particulate material with, for example, a polymer or wax to prolong or sustain release.

  The compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers may include polyvinylpyrrolidone (PVP), pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, this compound can be used as a class of biodegradable polymers useful in achieving controlled release of drugs (eg, polylactic acid, polyepsilon caprolactone, polyhydroxybutyric acid, polyorthoester, polyacetal, polydihydropyran, polycyanoacrylate, and It can also be combined with hydrogel cross-linked or amphiphilic block copolymers).

  Pharmaceutical formulations adapted for transdermal administration can be provided as individual patches intended to maintain intimate contact with the recipient's skin for an extended period of time. For example, the active ingredient can be delivered from the patch by iontophoresis generally described in Pharmaceutical Research, 3 (6), 318 (1986), which is incorporated herein by reference for such delivery systems.

  Pharmaceutical formulations adapted for topical administration can be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

  For the treatment of the eye or other external tissue (eg mouth and skin), the formulation can be applied as a topical ointment or cream. When formulated into an ointment, the active ingredient may be used with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

  Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier (especially an aqueous solvent).

  Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, tablets and mouthwashes.

  Pharmaceutical formulations adapted for nasal administration when the carrier is a solid include, for example, crude powders having a particle size in the range of 20 to 500 microns. The powder is administered in a manner that is inhaled by a nose from a container of powder held near the nose, ie, taken by rapid inhalation through the nasal passage. When the carrier is a liquid, suitable formulations for administration as a nasal spray or nasal spray include aqueous solutions or oil solutions of the active ingredient.

  Pharmaceutical formulations adapted for administration by inhalation include particulate dust or mist, which can be generated using various types of metered pressure aerosols, nebulizers or insufflators.

  Pharmaceutical formulations adapted for rectal administration may be provided as suppositories or enemas.

  Pharmaceutical formulations adapted for vaginal administration may be provided as vaginal suppositories, tampons, creams, gels, pastes, foams or spray formulations.

  Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may include antioxidants, buffers, bacteriostats, and solutes that are isotonic with the blood of the intended recipient; and Aqueous and non-aqueous sterile suspensions may be included which may include suspending and thickening agents. The formulation can be provided in unit dose or multi-dose containers (eg, sealed ampoules and vials) and can be stored in freeze-dried conditions (this is a sterile liquid carrier ( For example, only the addition of water for injection) is required). Ready-to-use injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

  In addition to the ingredients detailed above, the formulation may include other reagents customary in the art in view of the type of formulation in question. For example, formulations suitable for oral administration may include flavoring agents.

  The compounds of the invention and their salts, solvates and physiologically functional derivatives can be used alone or in combination with other therapeutic agents. The compound of Formula 1 and the other pharmaceutically active agent may be administered together or separately, and when administered separately, the administration may be performed simultaneously or sequentially in any order. The amounts of the compound of Formula 1 and other pharmaceutically active agents, as well as the appropriate timing of administration, can be selected to achieve the desired combined therapeutic effect. Administration of a compound of Formula 1, a salt, solvate or physiologically functional derivative thereof, in combination with another therapeutic compound or agent, (1) a single pharmaceutical composition comprising both compounds; or (2) A combination by combined administration with separate pharmaceutical compositions each containing one of the compounds may be used. Alternatively, the combination can be administered separately in a sequential manner in which one therapeutic agent is administered first and the other therapeutic agent is subsequently administered (or vice versa). Such continuous administration may be short or long in time intervals.

  The compounds of the invention can be used in the treatment of various disorders and conditions, for example, the compounds of the invention can be used in a variety of ways, including in the treatment (including prevention) of obesity and / or related diseases, disorders, or conditions. It can be used in combination with other suitable therapeutic agents. More specifically, the present invention includes the treatment (including prevention) of obesity. Other disorders, symptoms and / or diseases associated with obesity include diabetes, depression (major and bipolar), anxiety, hypertension, drug addiction, and arteriosclerosis.

One aspect of the present invention is a group consisting of a compound of formula 1 (a salt, solvate, or physiologically functional derivative thereof) and at least one agent or drug for treating obesity, diabetes, hypertension, and arteriosclerosis. In combination with at least one other species selected from. In particular, it may be a combination of a compound of formula 1 (its salt, solvate or physiologically functional derivative) with at least one chemical species for treating obesity, said chemical species being human ciliary body Neuroaffinity factor, CB-1 antagonist or inverse agonist (such as rimonabant), neurotransmitter reuptake inhibitor (such as sibutramine, bupropion, or bupropion hydrochloride, ladafaxin), lipase inhibitor (orlistat), MC4R agonist, 5-HT2c agonist , Ghrelin receptor antagonist, CCK-A receptor agonist, NPYY1 antagonist, PYY ³ _-36 and PPAR activator.

  The compounds of this invention can be made by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are described below and then specific compounds of the invention were prepared in the examples.

  In all of the examples below, protecting groups for sensitive or reactive groups are used according to the general principles of synthetic chemistry, as appropriate. Protecting groups are handled according to standard methods of organic synthesis (see T.W. Green and P.G.M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference for protecting groups). These groups are removed using methods that are readily apparent to those skilled in the art at convenient stages of compound synthesis. The choice of method and reaction conditions and order of their execution shall be consistent with the preparation of compounds of formula 1.

  One skilled in the art can understand whether a stereocenter exists in the compound of Formula 1. Accordingly, the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatography methods known in the art. it can. Resolution of the final product, intermediate or starting material can be accomplished by any suitable method known in the art. See, for example, E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry of Organic Compounds (Wiley-lnterscience, 1994), incorporated by reference for stereochemistry.

Scheme 1

The compounds of formula 1 of the present invention wherein either X or Z is NH and the other is N and Y is CH or CR ² , are represented by Scheme 1 (where A is CH ₂ ). ).

The preparation involves the nucleophilic aromatic substitution of a halodinitroaromatic compound with an appropriately substituted phenol. Typical reaction conditions involve the use of a base such as calcium carbonate (K ₂ CO ₃ ) and a solvent such as dimethylformamide at a temperature of 20-100 ° C. The dinitro compound is reduced under standard conditions, such as the use of a catalyst such as palladium on carbon and hydrogen, or the use of stannous chloride, iron, sodium sulfide or one of the other known methods. Other methods can be included. See, for example, Reductions in Organic Chemistry, Second Edition, Milos Hudlicky, ACS Monograph (1988).

  The resulting dianiline is condensed with an appropriately substituted carboxylic acid. This condensation may involve heating the dianiline in the presence of acid and in some cases may involve azeotropic removal of water. Saponification of the ester, such as treatment with a 10% aqueous solution of lithium hydroxide (LiOH) in tetrahydrofuran under standard conditions, yields the alcohol.

  Finishing to aldehydes is manganese dioxide, Swern oxidation, or one of many other known methods discussed in, for example, Transformations in Organic Chemistry, Second Edition, Richard C. LaRock (John Wiley and Sons: 1999). The process to reductive amination is carried out under standard conditions by treatment with the desired amine and sodium cyanoborohydride in methanol and acetic acid, or many other known for this reaction. For example, one of those discussed in Transformations in Organic Chemistry, Second Edition, Richard C. LaRock, (John Wiley and Sons, 1999) to obtain the desired compound.

Scheme 2

Equation 1 wherein, X is NH, Y is N, and Z is CH] Compound of likewise Scheme 2 (where A is CH ₂₎ can be prepared according to. The preparation involves nucleophilic aromatic substitution of halogenated aryl nitro compounds with appropriately substituted phenols. Typical reaction conditions involve the use of a base such as calcium carbonate (K ₂ CO ₃ ) and a solvent such as dimethylformamide at a temperature of 20-100 ° C. The aldehyde group is protected as an acetal under standard conditions (see, for example, Transformations in Organic Chemistry, Second Edition, Richard C. LaRock, John Wiley and Sons: 1999), then nitro is reduced under standard conditions to reduce the aniline intermediate. Get the body. Indazole is formed by treatment with sodium acetate and acetic anhydride under known conditions, followed by treatment with isoamyl nitrite in a solvent such as tetrahydrofuran, dioxane or other suitable solvent at a temperature of 20-100 ° C. . It is recommended that this reaction, or a subsequent reaction, such as the quenching of the next final step, be carried out under basic aqueous conditions to cleave the N-acetyl group. Alternatively, another step may be performed to remove acetate groups under standard conditions such as treatment with 10% aqueous LiOH in tetrahydrofuran. Unmasking of the aldehyde is performed under standard conditions, for example with polymer-supported tosylic acid and acetone, and then under standard conditions, for example treatment with the desired amine and sodium cyanoborohydride in methanol and acetic acid, or for this reaction Performed by one reductive amination of another known method (see, for example, Transformations in Organic Chemistry, Second Edition, Richard C. LaRock, (John Wiley and Sons: 1999)) to give the desired compound.

Method for testing compounds of the invention
material
LEADSeeker WGA® beads and GTPgS35 were purchased from Amersham Bioscience (Piscataway, NJ). GDP, Saponin®, DAMGO®, methionine-enkephalin, dinorphine A, NaCl and HEPES® were purchased from SIGMA (St Louis, MO). MgCl ₂ was purchased from JT Baker (Pillipsburg, NJ). Opioid membranes, hOPRD, hOPRK and hOPRM were prepared at GlaxoSmithkline (Harlow, UK).

Assay buffer: 20 mM HEPES, 10 mM MgCL ₂ , and 100 mM NaCl were dissolved in laboratory grade water, pH 7.4 (by KOH).

[ ³⁵ S] GTPγS binding assay measured by LEAD seeker SPA (384 well)
GTPgS ³⁵ is dissolved 1: 900 in half the required final assay volume (volume A) of assay buffer. The corresponding standard agonist, methionine-enkephalin (hOPRD), dinorphine A (hOPRK) or DAMGO (hOPRM) was added to give a solution concentration of 8 x [EC ₅₀ ], which was 4 x [EC ₅₀ for volume A ] Is the final assay concentration. Resuspend LEADSeeker beads in assay buffer to make a 40 mg / mL stock solution. Dissolve GDP in assay buffer at 1 mM. Beads (100 microgram / well final) are added to assay buffer containing saponin (60 microgram / mL) in half the final assay volume (volume B). Mix well by vortexing. Opioid membranes are added to each volume B to give a final assay concentration of 1.5 microgram / well (hOPRD), 1.0 microgram / well (hOPRK), and 1.5 microgram / well (hOPRM). After the bead / membrane solution (volume B) is continuously mixed for 30 minutes, GTPgS ³⁵ solution (volume A) is added at a ratio of 1: 1 using a stirring plate. Just before the bead / membrane solution is added to the GTPgS ³⁵ solution, GDP is added to volume B at 20 micromolar (10 micromolar, final assay concentration). Add the bead / membrane solution to the GTPgS ³⁵ solution in a 1: 1 ratio. Ten microliters of bead / membrane / GTPgS ³⁵ mix is added to the assay plate using Multidrop (Titertek®). Agitation of the solution is necessary so that the beads / membrane do not sink to the bottom. Seal the plate, centrifuge at 1000 rpm for 2 minutes, tap the side wall to stir and incubate at room temperature for 5 hours. The plate is then photographed using a Viewlux Plus® imager (Perkin Elmer).

Experimental part
Preparative HPLC general information : Compounds are protected by preparative HPLC at a flow rate of 20 ml / min (YMC Combiguard ODS-A, 10x10mm ID, 15/30 μm, 120Å pore size) and preparative columns (YMC Combiprep ODS-A, 30x50) (mm ID, 5 μm, 120 pore diameter). The eluent was a linear gradient of acetonitrile and water, both solutions containing 0.05% trifluoroacetic acid.

General method 1: A is CH ₂ Preparation of benzimidazole compound

Step 1 : Preparation of {4-[(3,4-dinitrophenol) oxy] phenyl} methanol

  4-Fluoro-1,2-dinitrobenzene (20.0 g, 107.5 mmol), 4- (hydroxymethyl) phenol (14.7 g, 118.2 mmol) and calcium carbonate (17.8 g, 129.0 mmol) in 250 ml dimethylformamide at room temperature For about 17 hours. The reaction was heated at 35 ° C. for 1.5 hours. Cesium carbonate (2 g, 6.14 mmol) was added and the reaction was heated at 45 ° C. for approximately 22 hours. The solid was filtered off and washed with ethyl acetate. The filtrate was diluted with water and extracted four times with ethyl acetate. The ethyl acetate layer was washed 5 times with a water / brine mixture. The washed aqueous layer was back extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give 14.1 g of {4-[(3,4-dinitrophenol) oxy] phenyl} methanol.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 4.51 (d, J = 5.9 Hz, 2 H) 5.27 (t, J = 5.6 Hz, 1 H) 7.20 (d, J = 8.5 Hz, 2 H) 7.27 (dd, J = 9.0, 2.7 Hz, 1 H) 7.43 (d, J = 8.8 Hz, 2 H) 7.76 (d, J = 2.7 Hz, 1 H) 8.25 (d, J = 9.0 Hz, 1 H) , (MH ₂ O) 273.1, 2.28 min (LC / MS method A).

Step 2 : Preparation of {4-[(3,4-diaminophenyl) oxy] phenyl} methanol

  {4-[(3,4-dinitrophenol) oxy] phenyl} methanol (3.73 g, 12.9 mmol) was added to 1.2 g of 10% Pd-supported carbon (100% ethyl acetate under a hydrogen balloon in approximately 100 ml of ethyl acetate ( Hydrogenated on wet, Degussa type) for 2.5 hours. An additional 600 mg of 10% Pd-supported carbon (wet, Degussa type) was added and the reaction was hydrogenated under a hydrogen balloon for 14.5 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in 1: 1 ethanol: ethyl acetate and hydrogenated over 1.2 g of 10% Pd on carbon (wet, Degussa) under a hydrogen balloon for 23.5 hours to leave the remaining reaction intermediate. Consumed. The catalyst was filtered off and the filtrate was concentrated to give 3.21 g of crude {4-[(3,4-diaminophenyl) oxy] phenyl} methanol, which was used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 4.39 (d, J = 5.6 Hz, 2 H) 5.05 (t, J = 5.9 Hz, 1 H) 6.04 (dd, J = 8.3, 2.7 Hz, 1 H) 6.19 (d, J = 2.7 Hz, 1 H) 6.46 (d, J = 8.3 Hz, 1 H) 6.79 (d, J = 8.8 Hz, 2 H) 7.19 (d, J = 8.8 Hz, 2 H) , (M + 1) 231.2, 0.92 min (LC / MS method A)
Step 3 : Preparation of [4- (1H-benzimidazol-5-yloxy) phenyl] methanol

{4-[(3,4-Diaminophenyl) oxy] phenyl} methanol (3.21 g crude material) was dissolved in 20 ml THF and 10 ml formic acid. The reaction was heated in a 100 ° C. oil bath for approximately 22 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed 5 times with saturated aqueous NaHCO ₃ . The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was dissolved in 30 ml of THF and 10 ml of 10% aqueous LiOH and heated at 100 ° C. for 30 minutes. The reaction was diluted with water and ethyl acetate. The organic layer was washed 3 times with brine, dried over MgSO ₄ and concentrated onto basic alumina under reduced pressure. The compound was purified by silica gel column chromatography (with dichloromethane gradient containing 100% dichloromethane to 10% (2M NH ₃ in methanol)) to give 1.26 g of [4- (1H-benzimidazol-5-yloxy) phenyl] methanol Got.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.43 (d, J = 5.4 Hz, 2 H) 5.11 (m, 1 H) 6.90 (m, 3 H) 7.13 (m, 1 H) 7.27 (m , 2 H) 7.55 (m, 1 H) 8.18 (m, 1 H) 12.41 (m, 1 H).

¹ H NMR (400 MHz, DMSO-D6 + 1 drop 30% w / w NaOD in D ₂ O) δ ppm 4.41 (s, 2 H) 6.79 (m, 1 H) 6.88 (d, J = 8.5 Hz, 2 H) 7.09 (m, 1 H) 7.25 (d, J = 8.1 Hz, 2 H) 7.50 (m, 1 H) 8.07 (m, 1 H), (M + 1) 241.1, 1.26 min (LC / MS method B).

Step 4 : Preparation of 4- (1H-benzimidazol-5-yloxy) benzaldehyde

[4- (1H-Benzimidazol-5-yloxy) phenyl] methanol (1.26 g) was dissolved in 70 ml of ethanol and 70 ml of chloroform and mixed with MnO ₂ (4.56 g, 52.5 mmol) in a 75 ° C. oil bath at 14 ° C. Heated for hours. An additional 1 g of MnO ₂ was added and the reaction was heated continuously for 3 hours. The reaction mixture was filtered through celite and concentrated under reduced pressure to give 1.26 g of 4- (1H-benzimidazol-5-yloxy) benzaldehyde.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 3.30 (s, 2 H) 6.99 (dd, J = 8.8, 2.4 Hz, 1 H) 7.06 (d, J = 8.8 Hz, 2 H) 7.35 (m , 1 H) 7.64 (d, J = 8.5 Hz, 1 H) 7.87 (d, J = 8.8 Hz, 2 H) 8.25 (s, 1 H) 9.88 (s, 1 H) 12.54 (s, 1 H), (M + 1) 239.2, 1.42 min (LC / MS method B).

Step 5 : Reductive amination to produce the final compound of Formula 1

4- (1H-benzimidazol-5-yloxy) benzaldehyde (50 mg, 0.21 mmol), primary or secondary amine (0.42 mmol), (if the amine is an acid salt, 1 equivalent of triethylamine was also added), and sodium cyano Borohydride (26 mg, 0.42 mmol) was stirred in methanol containing 4 ml of 4% acetic acid for approximately 18 hours. The reaction was quenched with approximately 0.5 ml of water and concentrated under a stream of nitrogen. The residue was dissolved in 1 ml 1M NaOH and approximately 3 ml ethyl acetate. The mixture was stirred vigorously using a Vortex-Genei stirrer. The organic layer was added to a Varian Chem Elute 1001 column, which was rinsed (gravity filtration) with 4-6 ml of ethyl acetate to elute the crude product. The eluate was concentrated. The residue was dissolved in 1.5-2 ml methanol and approximately 150 μl trifluoroacetic acid and purified using preparative HPLC.

General method 2: A is CH ₂ Of an indazole compound in which X is NH, Y is N and Z is CH

Step 1 : Preparation of 4-[(3-methyl-4-nitrophenyl) oxy] benzaldehyde

4-Hydroxybenzaldehyde (945 mg, 7.7 mmol), 4-fluoro-2-methyl-1-nitrobenzene (1.0 g, 6.4 mmol), and K ₂ CO ₃ (1.77 g, 12.8 mmol) in 100 mL of 55 mL dimethylformamide. For 18 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, extracted twice with 1N NaOH, and rinsed with brine. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 1.72 g of crude 4-[(3-methyl-4-nitrophenyl) oxy] benzaldehyde, which was used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 2.52 (s, 3 H) 7.10 (dd, J = 9.0, 2.7 Hz, 1 H) 7.22 (d, J = 2.7 Hz, 1 H) 7.28 (d , J = 8.8 Hz, 2 H) 7.97 (d, J = 8.8 Hz, 2 H) 8.09 (d, J = 9.0 Hz, 1 H) 9.96 (s, 1 H), (M + 1) 258.2, 1.42 min (LC / MS method A).

Step 2 : Preparation of 2- {4-[(3-methyl-4-nitrophenyl) oxy] phenyl} -1,3-dioxane

4-[(3-Methyl-4-nitrophenyl) oxy] benzaldehyde (1.72 g, 6.4 mmol), p-toluenesulfonic acid (120 mg, 0.64 mmol), and ethylene glycol (1.7 mL, 32 mmol) were added to Dean-Stark. Heated to reflux for 16 hours in 70 mL toluene in a round bottom flask equipped with a trap. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and extracted with 1N NaOH. The organic layer was dried over MgSO ₄ , filtered and concentrated to give 1.89 g of crude 2- {4-[(3-methyl-4-nitrophenyl) oxy] phenyl} -1,3-dioxalane. Was used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 2.50 (s, 3 H) 3.89-3.98 (m, 2 H) 3.99-4.08 (m, 2 H) 5.73 (s, 1 H) 6.93 (dd, J = 9.0, 2.9 Hz, 1 H) 7.07 (d, J = 2.9 Hz, 1 H) 7.14 (d, J = 8.5 Hz, 2 H) 7.50 (d, J = 8.5 Hz, 2 H) 8.05 (d, J = 9.0 Hz, 1 H), (M + 1) 302.1, 2.69 min (LC / MS method A).

Step 3 : Preparation of 4-{[4- (1,3-dioxolan-2-yl) phenyl] oxy} -2-methylaniline

A 500 mL round bottom flask containing 2- {4-[(3-methyl-4-nitrophenyl) oxy] phenyl} -1,3-dioxolane (1.89 g, 6.27 mmol) in 60 mL ethyl acetate was purged with nitrogen gas. Purge and treat with 10% palladium on carbon (650 mg, 0.63 mmol). A balloon containing H ₂ gas was connected and gas was bubbled through the solution while gas was let through the needle. The needle was removed and the reaction was stirred for 2 days under H ₂ atmosphere. The reaction was filtered through celite, concentrated and purified via silica gel column chromatography (0-100% ethyl acetate / hexane gradient) to give 1.24 g of 4-{[4- (1,3-dioxolane-2- Yl) phenyl] oxy} -2-methylaniline was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 2.01 (m, 3 H) 3.86-3.93 (m, 2 H) 3.95-4.03 (m, 2 H) 4.73 (s, 2 H) 5.62 (s, 1 H) 6.58-6.64 (m, 2 H) 6.65-6.68 (m, 1 H) 6.81 (d, J = 8.5 Hz, 2 H) 7.32 (d, J = 8.8 Hz, 2 H), (M + 1 ) 272.1, 1.58 minutes (LC / MS method A).

Step 4 : Preparation of 1-acetyl-5-{[4- (1,3-dioxolan-2-yl) phenyl] oxy} -1H-indazole

4-{[4- (1,3-Dioxolan-2-yl) phenyl] oxy} -2-methylaniline (1.24 g, 4.55 mmol) in 40 mL tetrahydrofuran using potassium acetate (490 mg, 5 mmol) at room temperature And then treated with acetic anhydride (1.42 mL, 15 mmol). After 10 minutes, the reaction was treated with isoamyl nitrite (0.915 mL, 6.8 mmol) and heated at reflux for 3 hours. Catalyst 18-crown-6 was added and the reaction was refluxed for 4 days. Upon cooling to room temperature, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted with ethyl acetate. The organic layer was rinsed with brine, dried over MgSO ₄ and concentrated. The crude material was purified via silica gel column chromatography (0-100% ethyl acetate gradient in hexanes) to give 0.835 g of 1-acetyl-5-{[4- (1,3-dioxolan-2-yl) phenyl ] Oxy} -1H-indazole was obtained.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 2.69 (s, 3 H) 3.90-3.96 (m, 2 H) 3.98-4.05 (m, 2 H) 5.69 (s, 1 H) 7.01 (d, J = 8.8 Hz, 2 H) 7.37 (dd, J = 9.0, 2.4 Hz, 1 H) 7.43 (d, J = 8.8 Hz, 2 H) 7.48 (d, J = 2.2 Hz, 1 H) 8.30 (d, J = 9.0 Hz, 1 H) 8.39 (s, 1 H), (M + 1) 325.1, 2.62 min (LC / MS method A).

Step 5 : Preparation of 4-[(1-acetyl-1H-indazol-5-yl) oxy] benzaldehyde

  Acetyl-5-{[4- (1,3-dioxolan-2-yl) phenyl] oxy} -1H-indazole (835 mg, 2.57 mmol) in 25 mL acetone retained on MP-TsOH (Argonaut, macroporous polymer) Tosylic acid, approximately 200 mg, 0.28 mmol) and stirred for 16 hours. The reaction was filtered and concentrated to give 4-[(1-acetyl-1H-indazol-5-yl) oxy] benzaldehyde quantitatively, which was used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 2.71 (s, 3 H) 7.13 (d, J = 8.8 Hz, 2 H) 7.44 (dd, J = 9.0, 2.4 Hz, 1 H) 7.67 (d , J = 2.4 Hz, 1 H) 7.91 (d, J = 8.5 Hz, 2 H) 8.36 (d, J = 8.8 Hz, 1 H) 8.44 (s, 1 H) 9.91 (s, 1 H), (M +1) 281.1, 2.53 minutes (LC / MS method A).

Step 6 : Reductive amination to produce compound

4-[(1-Acetyl-1H-indazol-5-yl) oxy] benzaldehyde (240 mg, 0.86 mmol) in 10 mL of 4% acetic acid methanolic solution is treated with primary or secondary amine (1.72 mmol). And then treated with sodium cyanoborohydride (108 mg, 1.72 mmol). The reaction was stirred until the starting aldehyde was consumed and the reaction was diluted with 1N sodium hydroxide and stirred until the intermediate acetate group was shown to be cleaved by LC / MS method A. The mixture was extracted with ethyl acetate and the organic layer was rinsed with brine, dried over MgSO ₄ and filtered. Treatment with 4N hydrochloric acid in dioxane followed by dilution with ethyl ether resulted in precipitation of typically pure desired product. Alternatively, purification was performed by preparative HPLC.

General method 3: A is CH ₂ And R ^Three Preparation of substituted benzimidazole compounds

Representative Example: N-{[4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) phenyl] methyl} -2,3-dihydro-1H-indene-2-amine = bis (trifluoro Acetate) (Example No. 86 herein)
Step 1 : Preparation of (4-hydroxy-2-nitrophenyl) formamide

  4-Amino-3-nitrophenol (36 g, 234 mmol) was divided into 3 batches (approximately 12 g each). Each batch was dissolved in 150 mL tetrahydrofuran and heated at 95 ° C. for 4 hours with 10 mL 96% formic acid. Three batches were combined and concentrated. The reaction proceeded to completion by approximately 10%, so the reaction mixture was dissolved in 100 mL 96% formic acid and heated at 110 ° C. After 30 minutes, a precipitate started to form, and 150 mL of tetrahydrofuran was added to ensure sufficient stirring. The reaction was heated at 110 ° C. for 15 hours. The reaction was concentrated and the residue was diluted with water. The resulting solid was collected by filtration. The solid was washed 3 times with water and dried in a vacuum oven at 110 ° C. for 18 hours to give 40.4 g of (4-hydroxy-2-nitrophenyl) formamide. (M-1) 181.0, 1.48 minutes (LC / MS method B).

Step 2 : Preparation of 4- (formylamino) -3-nitrophenyl acetate

  (4-Hydroxy-2-nitrophenyl) formamide (36.19 g, 198.8 mmol) and triethylamine (46 ml, 328 mmol) were dissolved in tetrahydrofuran and the reaction flask was cooled in an ice bath. Acetyl chloride (15.6 ml, 218.7 mmol) was added via an addition funnel over 10 minutes. The reaction was allowed to warm to room temperature until complete (as judged by LC-MS) and concentrated. The residue was diluted with water. The resulting solid was collected by filtration. The solid was washed twice with water and then dried in a vacuum oven at 110 ° C. for approximately 18 hours to give 23.5 g of 4- (formylamino) -3-nitrophenyl acetate. (M-1) 224.0, 1.98 min (LC / MS method B).

Step 3 : Preparation of 3-amino-4- (formylamino) phenyl acetate

  4- (Formylamino) -3-nitrophenyl acetate (13.5 g, 60.3 mmol; divided into 1 g, 5 g and 7.5 g batches) was dissolved in a minimum amount of ethyl acetate. This solution was hydrogenated on a Parr hydrogenator through 10% Pd-supported carbon (wet, degussa type) at 40 psi for 1 hour. The catalyst was removed by filtering the reaction through celite. The filtrate was concentrated to give 10.3 g of 3-amino-4- (formylamino) phenyl acetate. (M + 1) 195.1, 1.31 min (LC / MS method A).

Step 4 : Preparation of 1H-benzimidazol-5-yl acetate

3-Amino-4- (formylamino) phenyl acetate (10.3 g, 53.1 mmol) was dissolved in approximately 100 mL of glacial acetic acid and heated at 65 ° C. for approximately 18 hours. The reaction was concentrated and dried under vacuum. The residue was dissolved in ethyl acetate and washed with saturated NaHCO ₃ . The organic layer was dried over MgSO ₄ and concentrated to give 6.89 g of 1H-benzimidazol-5-yl acetate. (M + 1) 177.1, 1.02 minutes (LC / MS method B)
Step 5 : Mixture of 1- (triphenylmethyl) -1H-benzimidazol-5-ol and 1- (triphenylmethyl) -1H-benzimidazol-6-ol

1H-Benzimidazol-5-yl acetate (6.89 g, 39.1 mmol), trityl chloride (9.82 g, 43.1 mmol) and triethylamine (11 ml, 78 mmol) were stirred in 200 mL of tetrahydrofuran for 3 days. 40 mL of 10% aqueous LiOH was added and the reaction was heated at 85 ° C. for 2 hours. The reaction was cooled to room temperature and diluted with water and ethyl acetate. The pH was adjusted to approximately pH = 3 with 1N HCl. A small amount of fine solid was filtered off and the filtrate was extracted three times with ethyl acetate. The organic layers were combined and washed with brine. The organic layer was dried over MgSO ₄ and concentrated. The residue was dissolved with a minimum amount of dichloromethane and a portion was added to the chromatographic alumina column when a precipitate formed. The alumina was washed with a large amount of ethyl acetate and methanol. The filtrate and the remainder of the crude product were concentrated together. The crude product was triturated with diethyl ether to precipitate the solid. The solid was collected by filtration and washed with ether to give a mixture of 1- (triphenylmethyl) -1H-benzimidazol-6-ol and 1- (triphenylmethyl) -1H-benzimidazol-5-ol . (MH) 377.2, 2.58 min, and its isomer (at 2.66 min) (LC / MS method B).

Step 6 : 4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) benzaldehyde

Mixture of 1- (triphenylmethyl) -1H-benzimidazol-5-ol and 1- (triphenylmethyl) -1H-benzimidazol-6-ol (750 mg, 2.0 mmol), 4-fluoro-3- (methyl Oxy) benzaldehyde (461 mg, 3.0 mmol) and cesium carbonate (972 mg, 3.0 mmol) were heated in dimethylformamide at 80 ° C. for 2 hours. The reaction was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over MgSO ₄ , concentrated and dried under vacuum for approximately 18 hours. The residue was dissolved in 15 mL of tetrahydrofuran and stirred with 5 mL of 4N HCl in dioxane for 4 days. The reaction was concentrated and purified by preparative HPLC. Pure fractions were diluted with 1N NaOH to make basic and then extracted twice with ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated to give 4- (1H-benzimidazol-5-yloxy) -3- (methyloxy) benzaldehyde. (M + 1) 269.0, 1.34 minutes (LC / MS method B)
Step 7 : N-{[4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) phenyl] methyl} -2,3-dihydro-1H-indene-2-amine = bis (trifluoroacetate (Example number 86)

  The final compound was prepared using General Method 1, Step 5, using the appropriate aldehyde and amine.

General method 4: A is CH ₂ Preparation of benzimidazole compound

Representative example : N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2,3-dihydro-1H-inden-2-amine dihydrochloride (Example No. 26).

Step 1 : Preparation of 4-[(4-amino-3-nitrophenyl) oxy] benzaldehyde

  4-Amino-3-nitrophenol (25 g, 162 mmol), 4-fluorobenzaldehyde (19.1 g, 154 mmol) and cesium carbonate (58 g, 178 mmol) in dimethylformamide at 85 ° C. for 20 minutes, then approximately 45 ° C. Stir for 18 hours. The reaction was cooled to room temperature, filtered through celite and eluted with ethyl acetate. Water, brine and ethyl acetate were added to the filtrate which was then filtered through an Alltech 75 mL Extract-Clean® filter column packed with glass wool. The filtrate was divided into two portions, each extracted with ethyl acetate and washed 4 times with brine. The organic layers were combined, dried over magnesium sulfate, concentrated onto basic alumina and purified by silica gel column chromatography (ethyl acetate 0-100% in hexane) to yield 23 g of 4-[(4-amino-3- Nitrophenyl) oxy] benzaldehyde was obtained. (M + 1) 259.0, 2.39 min (LC / MS method A).

Step 2 : Preparation of {4-[(4-formylphenyl) oxy] -2-nitrophenyl} formamide

  4-[(4-Amino-3-nitrophenyl) oxy] benzaldehyde (1.4 g, 5.4 mmol), 10 mL of 96% formic acid and 25 mL of tetrahydrofuran were heated at reflux for approximately 18 hours. The reaction was concentrated and the residue was heated to reflux in 96% formic acid for 6 hours. The reaction mixture was concentrated to give {4-[(4-formylphenyl) oxy] -2-nitrophenyl} formamide. (M-1) 285.1, 2.22 min (LC / MS method A).

Step 3 : 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [(4-{[4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3 Of -Nitrophenyl] oxy} phenyl) methyl] carbamate

  {4-[(4-Formylphenyl) oxy] -2-nitrophenyl} formamide (530 mg, 1.85 mmol), amine (in this case 2-aminoindane, 300 microliters, 2.3 mmol) and sodium cyanoborohydride ( 151 mg, 1.4 mmol) was stirred in 25 mL 4% methanol in methanol and 5 mL ethyl acetate for 67.5 hours. The reaction mixture was concentrated. The residue was dissolved in 5 mL 1M NaOH and approximately 5 mL ethyl acetate. The mixture was stirred vigorously using a vortex genie stirrer. The organic layer was applied to a Varian Chem Elute® 1010 column, which was rinsed (gravity filtration) with 4-6 mL of ethyl acetate to elute the crude product. The eluate was concentrated and then dissolved in 15 mL of tetrahydrofuran. Di-tert-butyl carbonate (0.64 mL, 2.8 mmol), triethylamine (518 microliters, 3.7 mmol) and 15 mg of 4- (dimethylamino) pyridine were added and stirred for approximately 18 hours. The reaction was quenched with 5 mL of 1N HCl and stirred vigorously. The reaction mixture was passed through a Varian Chem Elute® 1010 column and then rinsed with ethyl acetate. The eluate was concentrated onto basic alumina and purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [ (4-{[4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3-nitrophenyl] oxy} phenyl) methyl] carbamate was obtained. (M + 1) 576.2, 3.47 min (LC / MS method A).

Step 4 : 1,1-dimethylethyl = [2-amino-4-({4-[(2,3-dihydro-1H-inden-2-yl {[(1,1-dimethylethyl) oxy] carbonyl} Preparation of amino) methyl] phenyl} oxy) phenyl] carbamate

  1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [(4-{[4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3-nitrophenyl ] Oxy} phenyl) methyl] carbamate (647 mg, 1.12 mmol) in ethyl acetate was hydrogenated over approximately 50 mg of 10% Pd / carbon (wet, degussa type) under hydrogen atmosphere for approximately 18 hours. The catalyst was filtered off and the filtrate was concentrated. The reaction was purified by silica gel column chromatography (0-100% ethyl acetate in hexane) to give 1,1-dimethylethyl = [2-amino-4-({4-[(2,3-dihydro-1H-indene -2-yl {[(1,1-dimethylethyl) oxy] carbonyl} amino) methyl] phenyl} oxy) phenyl] carbamate was obtained. (M + 1) 546.3, 3.15 min (LC / MS method A).

Step 5 : 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [(4-{[4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3 -(Formylamino) phenyl] oxy} phenyl) methyl] carbamate

Formic acetic anhydride was prepared by adding 96% formic acid (1.24 ml, 32.2 mmol) to acetic anhydride (1.52 ml, 16.1 mmol) and stirring for 1 hour (reference: Org. Process Research). & Development, 2000, 4, p. 567-570). Formic acid acetic anhydride (0.16 ml, 0.87 mmol) was added to 1,1-dimethylethyl [2-amino-4-({4-[(2,3-dihydro-1H-inden-2-yl { To a solution of [(1,1-dimethylethyl) oxy] carbonyl} amino) methyl] phenyl} oxy) phenyl] carbamate (430 mg, 0.79 mmol). The reaction mixture was stirred for 30 minutes, then quenched with 2 mL of 1N NaOH and stirred vigorously. The reaction was passed through a Varian Chem Elute® 1010 tube pretreated with 2 mL of 1N NaOH for 5 minutes. The tube was eluted with ethyl acetate. The eluate was dried over MgSO ₄ and concentrated to 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [(4-{[4-({[(1,1-dimethyl Ethyl) oxy] carbonyl} amino) -3- (formylamino) phenyl] oxy} phenyl) methyl] carbamate was obtained. (M-1) 572.0, 2.93 minutes (LC / MS method B)
Step 6: Preparation of N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2,3-dihydro-1H-indene-2-amine dihydrochloride (Example No. 26)

1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl [(4-{[4-({[(1,1-dimethylethyl) oxy] carbonyl} amino) -3- (formyl Amino) phenyl] oxy} phenyl) methyl] carbamate (365 mg, 0.637 mmol) was dissolved in 20 mL methylene chloride and stirred with 4 mL trifluoroacetic acid for approximately 18 hours. The reaction was concentrated and purified using preparative HPLC. Pure fractions were combined, diluted with ethyl acetate and washed with 1N NaOH. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and concentrated. The residue was dissolved in ethyl acetate. 4N HCl in dioxane was added and N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2,3-dihydro-1H-inden-2-amine dihydrochloride was filtered to remove white Collected as sediment. The solid was dissolved in methanol, concentrated onto basic alumina and purified by column chromatography using an ISCO® amine functionalized silica column. (Dichloromethane to 5% methanol). The purified material was dissolved in a minimum of methanol. HCl (4N in dioxane) is added to the solution and it is concentrated to N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2,3-dihydro-1H-indene-2- Amine dihydrochloride (Example No. 26) was obtained.

General method 5: A is CH ₂ And R ^Three Of benzimidazole compounds in which is substituted

Representative Example : N-{[4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) phenyl] methyl} -2,3-dihydro-1H-indene-2-amine = bis (trifluoro Acetate) (Example No. 86)
Step 1: Preparation of 4-[(4-amino-3-nitrophenyl) oxy] -3- (methyloxy) benzaldehyde

4-amino-3-nitrophenol (2 g, 13 mmol), 4-fluoro-3- (methyloxy) benzaldehyde (2 g, 13 mmol) and Cs ₂ CO ₃ (5.1 g, 15.6 mmol) in dimethylformamide at 100 ° C. And stirred for approximately 18 hours. The reaction was filtered through an Alltech 75 mL Extract-Clean® filter column packed with glass wool and eluted with ethyl acetate. The eluate was stirred with 5 mL of water and then passed through a Varian Chem Elute® 1010 column, which was rinsed (gravity filtration) with 4-6 ml of ethyl acetate. The eluate was dried over MgSO ₄ , concentrated onto basic alumina and purified by silica gel column chromatography (hexane / ethyl acetate gradient) to give 4-[(4-amino-3-nitrophenyl) oxy] -3- ( Methyloxy) benzaldehyde was obtained. (M + 1) 289.0, 2.26 min (LC / MS method A).

Step 2: Preparation of 4-{[4- (1,3-Dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitroaniline

4-[(4-Amino-3-nitrophenyl) oxy] -3- (methyloxy) benzaldehyde (2.42 g, 8.4 mmol), ethylene glycol (4 ml) and p-toluenesulfonic acid (50 mg) in 50 mL of toluene Was heated at 125 ° C with a Dean-Stark trap for approximately 18 hours. The reaction mixture was diluted with ethyl acetate and washed twice with saturated NaHCO ₃ . The aqueous layer was extracted with ethyl acetate. The organic layers are combined, dried over MgSO ₄ and concentrated to give 4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitroaniline. It was. (M + 1) 332.9, 2.13 minutes (LC / MS method B)
Step 3: (4-{[4- (1,3-Dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitrophenyl) formamide

Formic acid acetic anhydride was prepared by adding 96% formic acid (0.702 ml, 18.3 mmol) to acetic anhydride (0.863 ml, 9.1 mmol) and stirring for 30 minutes. Diisopropylethylamine (3.2 ml, 18.3 mmol) and 4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitroaniline (2.53 g, 7.62 mmol) Of tetrahydrofuran was added to formic acid acetic anhydride. The reaction was stirred for approximately 18 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N NaOH. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography to give (4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitrophenyl) formamide. . (M + 1) 360.8, 2.31 min (LC / MS method B).

Step 4: (2-Amino-4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} phenyl) formamide

  (4-{[4- (1,3-Dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} -2-nitrophenyl) formamide (430 mg) in approximately 75 mL of ethyl acetate under hydrogen atmosphere And hydrogenated on approximately 100 mg of 10% Pd-supported carbon (wet, degussa type) for 3 days. The catalyst was filtered off and the filtrate was concentrated to give (2-amino-4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} phenyl) formamide. This was used without further purification. (M + 1) 330.9, 1.79 min (LC / MS method B).

Step 5: 4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) benzaldehyde and 5-{[4- [bis (methyloxy) methyl] -2- (methyloxy) phenyl] oxy}- Preparation of 1H-benzimidazole

(2-Amino-4-{[4- (1,3-dioxolan-2-yl) -2- (methyloxy) phenyl] oxy} phenyl) formamide (408 mg) in 10 mL dichloromethane and 2 mL trifluoroacetic acid For 2 hours. The reaction mixture was concentrated. Since the reaction was not complete, the residue was dissolved in raw trifluoroacetic acid and stirred at 45 ° C. for approximately 18 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (gradient of dichloromethane in methanol / dichloromethane up to 10% 2N NH ₃ ) to give 4- (1H-benzimidazol-5-yloxy) -3- (methyloxy) benzaldehyde And a mixture of 5-{[4- [bis (methyloxy) methyl] -2- (methyloxy) phenyl] oxy} -1H-benzimidazole was obtained and treated in the next step. (M + 1) 269.0, 1.21 min, (M + 1) 315.1, 1.50 min (LC / MS method A).

Step 6: N-{[4- (1H-Benzimidazol-5-yloxy) -3- (methyloxy) phenyl] methyl} -2,3-dihydro-1H-inden-2-amine = bis (trifluoroacetate (Example number 86)

  N-{[4- (1H-benzimidazol-5-yloxy) -3- (methyloxy) phenyl] methyl} -2,3-dihydro-1H-inden-2-amine is 4- (1H-benzimidazole Mixture of 5-5-yloxy) -3- (methyloxy) benzaldehyde and 5-{[4- [bis (methyloxy) methyl] -2- (methyloxy) phenyl] oxy} -1H-benzimidazole and general method 1. Prepared using the procedure of Step 5 (where 2-aminoindane is the amine).

General method 6: R ^Three With substitution and A is CH ₂ Preparation of benzimidazole compound

Representative Example: N-{[4- (1H-Benzimidazol-5-yloxy) -3-chlorophenyl] methyl} -2,3-dihydro-1H-inden-2-amine = trifluoroacetate (Example No. 77 Preparation of
Step 1: Preparation of 4-[(4-amino-3-nitrophenyl) oxy] -3-chlorobenzaldehyde

4-[(4-Amino-3-nitrophenyl) oxy] -3-chlorobenzaldehyde was prepared from 3-chloro-4-fluorobenzaldehyde and 4-amino-3-nitrophenol using method 5, step 1 procedure. . (M-1) 291.1, 2.59 minutes (LC / MS method A)
Step 2: 4-{[2-Chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -2-nitroaniline

120 ml of 4-[(4-amino-3-nitrophenyl) oxy] -3-chlorobenzaldehyde (1.16 g, 5.3 mmol), ethylene glycol (5 ml) and p-toluenesulfonic acid (50 mg) in 150 mL of toluene. Heat at 24 ° C. using a Dean-Stark trap for 24 hours. The reaction mixture was diluted with ethyl acetate and washed twice with 1N NaOH. The organic layer was dried over MgSO ₄ and concentrated to give 4-{[2-chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -2-nitroaniline. (M + 1) 336.9, 2.60 min (LC / MS method B)
Step 3: 4-{[2-Chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -1,2-benzenediamine

4-{[2-Chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -2-nitroaniline (1.41 g) is dissolved in 100 mL ethyl acetate and 100 mg 10% Pd / carbon Hydrogenated under a balloon of H ₂ gas on (wet, Degussa type). After 24 hours, the reaction was filtered through celite and concentrated to give 4-{[2-chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -1,2-benzenediamine. This was used without further purification. (M + 1) 306.9, 1.57 minutes (LC / MS method B)
Step 4: 4- (1H-Benzimidazol-5-yloxy) -3-chlorobenzaldehyde

Crude 4-{[2-chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -1,2-benzenediamine was heated to reflux in 5 mL of trimethyl orthoformate for 2 hours. The reaction mixture was then concentrated and purified by preparative HPLC to remove the dioxolane protecting group simultaneously. The HPLC fractions were combined, diluted with 1N NaOH, extracted with ethyl acetate, dried over MgSO ₄ and concentrated to give 4- (1H-benzimidazol-5-yloxy) -3-chlorobenzaldehyde. (M + 1) 272.9, 1.65 minutes (LC / MS method B)
Step 5: Preparation of N-{[4- (1H-benzimidazol-5-yloxy) -3-chlorophenyl] methyl} -2,3-dihydro-1H-inden-2-amine = trifluoroacetate (Example No. 77)

  The final compound was prepared using general method 1, step 5, using the appropriate aldehyde and amine.

General method 7: A is CHCH _Three Preparation of benzimidazole compound

Representative Example: Preparation of {1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethyl} (cyclohexylmethyl) amine bis (trifluoroacetate) (Example No. 72)
Step 1 : Preparation of 1- {4-[(4-amino-3-nitrophenyl) oxy] phenyl} ethanone

1- (4-Fluorophenyl) ethanone (1.79 g, 12.9 mmol), 4-amino-3-nitrophenol (2 g, 12.9 mmol) and Cs ₂ CO ₃ (4.65 g, 14.3 mmol) in 50 mL dimethylformamide Stir at 80 ° C. for 24 hours. The solid was removed by filtration. The filtrate was diluted with ethyl acetate and washed 3 times each with water and brine. The aqueous layer was back extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and concentrated onto basic alumina. The crude product was purified by silica gel column chromatography (hexane vs. ethyl acetate gradient) to give 1- {4-[(4-amino-3-nitrophenyl) oxy] phenyl} ethanone. (M + 1) 272.9, 2.42 min (LC / MS method B).

Step 2: Preparation of 1- {4-[(3,4-diaminophenyl) oxy] phenyl} ethanol

1- {4-[(4-Amino-3-nitrophenyl) oxy] phenyl} ethanone (437 mg) dissolved in 1: 1 ethyl acetate: methanol and over 500 mg of 10% Pd / carbon (wet, degussa type) And hydrogenated under H ₂ gas atmosphere. After 24 hours, the reaction was filtered through celite and concentrated to give crude 1- {4-[(3,4-diaminophenyl) oxy] phenyl} ethanol, which was used without further purification. (M + 1) 245.2, 1.05 minutes (LC / MS method A)
Step 3: Preparation of 1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethanol

Crude 1- {4-[(3,4-diaminophenyl) oxy] phenyl} ethanol was dissolved in 10 mL tetrahydrofuran and 5 mL 88% formic acid and heated at 100 ° C. for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and saturated NaHCO ₃ . The organic layer was separated and washed twice with saturated NaHCO ₃ . The organic layer was dried over MgSO ₄ and concentrated. The residue was dissolved in 10 mL of THF and heated at 100 ° C. with 5 mL of 10% aqueous LiOH for 2 hours. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The organic layers were combined, dried over MgSO ₄ and concentrated to give crude 1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethanol, which was processed in the next step without further purification. . (M + 1) 239.0, 1.39 min (LC / MS method B).

Step 4 : Preparation of 1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethanone

Crude 1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethanol was dissolved in 75 mL of 1: 1 ethanol: chloroform and 80 with MnO ₂ (1.4 g, 10 eq based on starting material from Step 2). Stir at ℃ for approximately 18 hours. A second 1.4 gofMnO ₂ was added and the reaction was heated for an additional 24 hours. A third time 1.4 g of MnO ₂ was added and the reaction was heated for an additional 24 hours. The reaction was filtered through celite and concentrated onto basic alumina. The crude product was purified by silica gel column chromatography to give 1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethanone and impurities, which were treated in the next step. (M + 1) 253.0, 1.41 minutes (LC / MS method B)
Step 5 : Preparation of {1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethyl} (cyclohexylmethyl) amine bis (trifluoroacetate) (Example No. 72)

1- [4- (1H-Benzimidazol-5-yloxy) phenyl] ethanone (35 mg, with impurities) was heated in ethanol with excess (cyclohexylmethyl) amine (0.084 ml) at 80 ° C. Azeotropic removal was performed. Upon completion of the reaction and drying, more ethanol was added. This was done three times. The residue after the last drying was dissolved in 25 mL ethanol. NaBH ₄ (21 mg, 0.56 mmol) was added and the reaction was stirred. The reaction mixture was concentrated, diluted with 1N NaOH and ethyl acetate and stirred vigorously. The organic layer was added to a Varian Chem Elute® 1001 column, which was rinsed with ethyl acetate (gravity filtration) to elute the crude product. The eluate was concentrated and purified by preparative HPLC to give {1- [4- (1H-benzimidazol-5-yloxy) phenyl] ethyl} (cyclohexylmethyl) amine = bis (trifluoroacetate).

General method 8: R ^Four With substitution and A is CH ₂ Preparation of benzimidazole compound

Representative example : N-({4-[(4,6-difluoro-1H-benzimidazol-5-yl) oxy] phenyl} methyl) -2,3-dihydro-1H-inden-2-amine = bis ( Preparation of (trifluoroacetate) (Example No. 88)
Step 1 : Preparation of 4-[(3-amino-2,6-difluoro-4-nitrophenyl) oxy] benzaldehyde

2,3,4-trifluoro-6-nitroaniline (5 g, 26 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.6 mmol) and Cs ₂ CO ₃ (10.5 g, 32.6 mmol) in 150 mL dimethylformamide Stir at 65 ° C. for approximately 18 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate. The organic layers were combined, washed 5 times with brine, dried over Mg ₂ SO ₄ and concentrated onto basic alumina. The residue was purified by silica gel column chromatography (gradient from hexane to ethyl acetate) to give 4-[(3-amino-2,6-difluoro-4-nitrophenyl) oxy] benzaldehyde. ¹ H NMR (400 MHz, DMSO-d ₆ ) delta ppm 7.29 (d, J = 8.8 Hz, 2 H) 7.46 (s., 2 H) 7.93 (d, J = 8.8 Hz, 2 H) 7.98 (dd, J = 11.0, 1.7 Hz, 1 H) 9.93 (s., 1 H).

Step 2 : 1,1-dimethylethyl = ({4-[(3-amino-2,6-difluoro-4-nitrophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-yl Preparation of carbamate

4-[(3-Amino-2,6-difluoro-4-nitrophenyl) oxy] benzaldehyde (1 g, 3.4 mmol), 2-aminoindane (543 mg, 4.1 mmol) and sodium cyanoborohydride (276 mg, 4.1 mmol) The mixture was stirred in 4% acetic acid methanol solution for approximately 18 hours and concentrated. The residue was dissolved in ethyl acetate and 1N NaOH. The organic layer was washed twice with 1N NaOH. The organic layer was then vigorously stirred with 50 mL of 1N NaHCO ₃ and di-tert-butyl dicarbonate (890 mg, 4.08 mmol) and stirred for approximately 18 hours. An additional 150 mg of di-tert-butyl dicarbonate was added and the reaction was stirred for an additional 2 hours. An additional 150 mg of di-tert-butyl dicarbonate was added and the reaction was stirred for an additional hour. The organic layer was separated and washed once with 1N NaOH and twice with brine. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (hexane vs. ethyl acetate gradient) to give 1,1-dimethylethyl = ({4-[(3-amino-2,6-difluoro-4-nitrophenyl) oxy] phenyl } Methyl) 2,3-dihydro-1H-inden-2-ylcarbamate was obtained. (M + H-Boc) 412.2, 3.27 min (LC / MS method B).

Step 3 : 1,1-dimethylethyl = ({4-[(3,4-diamino-2,6-difluorophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-ylcarbamate Preparation of

  1,1-dimethylethyl = ({4-[(3-amino-2,6-difluoro-4-nitrophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-ylcarbamate ( 114 mg) was dissolved in ethyl acetate and hydrogenated on a Parr hydrogenator through 10% Pd-supported carbon (wet, Degussa type) at 45 psi. The catalyst was removed by filtration through celite. The filtrate was concentrated to give [2-amino-4-({4-[(2,3-dihydro-1H-inden-2-ylamino) methyl] phenyl} oxy) -3,5-difluorophenyl] amine This was used without further purification.

Step 4 : N-({4-[(4,6-Difluoro-1H-benzimidazol-5-yl) oxy] phenyl} methyl) -2,3-dihydro-1H-indene-2-amine = bis (tri Preparation of (fluoroacetate) (Example No. 88)

  1,1-dimethylethyl = ({4-[(3,4-diamino-2,6-difluorophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-ylcarbamate (Step 3 The crude material obtained from was dissolved in 10 mL 96% formic acid and heated at 100 ° C. for 4 days. The reaction mixture was concentrated and purified by preparative HPLC to give N-({4-[(4,6-difluoro-1H-benzimidazol-5-yl) oxy] phenyl} methyl) -2,3-dihydro-1H -Indene-2-amine bis (trifluoroacetate) was obtained.

General method 9: X or Z is NCH _Three And A = CH ₂ Preparation of benzimidazole compound

Representative Example : (4,4-Dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-6-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 70)
(4,4-Dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 71)
Step 1 : Preparation of 1,1-dimethylethyl = {[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} (4,4-dimethylcyclohexyl) carbamate

Crude N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -4,4-dimethylcyclohexaneamine (Example 2) (prepared using General Method 1) dissolved in ethyl acetate And stirred with di-tert-butyl dicarbonate (403 mg, 1.85 mmol, 1.1 eq based on starting with 1.68 mmol of aldehyde in step 5 of general method 1) and saturated aqueous NaHCO ₃ solution. After 1 hour, the organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO ₄ and concentrated. The residue was dissolved in tetrahydrofuran and heated at 90 ° C. with 1N LiOH aqueous solution for 2 hours. After the reaction cooled to room temperature, the reaction was diluted with water, extracted twice with ethyl acetate, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (from CH ₂ Cl ₂ to CH ₂ Cl ₂ containing 10% methanol (2% NH ₃₎₎ 1,1- dimethylethyl = {[4- (1H- benzimidazole - 5-yloxy) phenyl] methyl} (4,4-dimethylcyclohexyl) carbamate was obtained. (MH) 448.2, 2.82 minutes, (LC / MS method B)
Step 2: (4,4-Dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-6-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 70) and (4,4 -Dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 71)

1,1-dimethylethyl = {[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} (4,4-dimethylcyclohexyl) carbamate (389 mg, 0.87 mmol), dimethyl sulfate (0.166 mL, 1.7 mmol) And 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.155 mL, 1.0 mmol) were stirred in dichloromethane for approximately 18 hours. The reaction was diluted with water and concentrated with dichloromethane. The organic layer was washed with 1N NaOH, dried over MgSO ₄ and concentrated. The residue was purified by silica gel column chromatography (gradient from CH ₂ Cl ₂ to CH ₂ Cl ₂ containing 10% methanol (2% NH ₃₎₎ 1,1-Dimethylethyl = (4,4-dimethylcyclohexyl) ({4-[(1-Methyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) carbamate and 1,1-dimethylethyl = (4,4-dimethylcyclohexyl) ({4-[(1- Methyl-1H-benzimidazol-6-yl) oxy] phenyl} methyl) carbamate was obtained. The mixture was separated on a chiral OD column at 140 bar and 40 ° C. using 13% methanol and CO ₂ as mobile phases. The separated isomers were each treated with 3 mL of dioxane containing 4N HCl for approximately 18 hours. The separated compound was collected as a white solid by filtration. These two isomers:
(4,4-dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-6-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 70), and
(4,4-Dimethylcyclohexyl) ({4-[(1-methyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) amine hydrochloride (Example No. 71)
The structural identity of was confirmed by COZY and ROESY NMR.

General method 10: R ^Four Is 4-position CF _Three And R ⁶ Is CF _Three And A is CH ₂ Preparation of benzimidazole compound

Step 1: Preparation of N- [4-fluoro-2-nitro-6- (trifluoromethyl) phenyl] acetamide

A solution of 4-fluoro-2- (trifluoromethyl) aniline (5.0 g, 27.91 mmol) in acetic anhydride (25 mL) was stirred at ambient temperature for 3 hours to produce a white needle precipitate. The reaction mixture is poured into ice water, filtered and then dried to give 6.0 g of N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide as an off-white solid that is further purified. Used without. The N- [4-fluoro-2- (trifluoromethyl) phenyl] acetamide (2.0 g, 9.04 mmol) was dissolved in concentrated H ₂ SO ₄ (15 mL) and cooled to 0 ° C. using an ice bath. 70% HNO ₃ (1.5 mL) was added dropwise and the reaction was stirred at 0 ° C. for 30 minutes and then at ambient temperature for 3 hours. The reaction mixture was poured into ice water, filtered and dried to give 2.4 g of the desired N- [4-fluoro-2-nitro-6- (trifluoromethyl) phenyl] acetamide.

¹ H NMR (400 MHz, CDCl ₃ ) delta ppm 2.21 (s, 3 H) 7.30 (br.s, 1 H) 7.68 (dd, J = 7.45; 3.05 Hz, 1 H) 7.86 (dd, J = 7.2; 3.05 Hz, 1 H), (M + H) 267.1, 1.57 min (LC / MS method A).

Step 2: Preparation of N- [4-[(4-formylphenyl) oxy] -2-nitro-6- (trifluoromethyl) phenyl] acetamide

N- [4-Fluoro-2-nitro-6- (trifluoromethyl) phenyl] acetamide (1.5 g, 5.63 mmol), Cs ₂ CO ₃ (4.59 g, 14.09 mmol), and 4-hydroxybenzaldehyde (0.757 g, A solution of 6.20 mmol) in dimethyl sulfoxide (10 mL) was heated at 80 ° C. for 2 hours and then cooled. H ₂ O was added and the organics were extracted with ethyl acetate (2 × 50 mL). The combined organic layers were then washed with 1 × brine, then dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography on silica gel eluting with 2: 1 hexane / ethyl acetate N- [4-[(4-formylphenyl) oxy] -2-nitro-6- (trifluoromethyl) phenyl] Acetamide was obtained as an orange solid (0.922 g; 44% yield).

¹ H NMR (400 MHz, CDCl ₃ ) delta ppm 7.20 (m, 2 H) 7.37 (br.s, 1 H) 7.60 (d, J = 2.69 Hz, 1 H) 7.72 (d, J = 2.93 Hz, 1 H) 7.97 (m, 2H) 10.0 (s, 1H).

Step 3: Preparation of 2,2,2-trifluoro-N- [4-[(4-formylphenyl) oxy] -2-nitro-6- (trifluoromethyl) phenyl] acetamide

A solution of N- [4-[(4-formylphenyl) oxy] -2-nitro-6- (trifluoromethyl) phenyl] acetamide (0.750 g, 2.04 mmol) in concentrated HCl (2 mL) and ethanol (2 mL) Was refluxed overnight, cooled, and then slowly poured into a solution of saturated NaHCO ₃ . The organics were extracted with ethyl acetate (2x25mL). The combined organic layers were washed with H ₂ O, washed once with brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. To the residue was added trifluoroacetic anhydride and the mixture was stirred for 16 hours at ambient temperature. The reaction mixture was slowly poured into cold saturated NaHCO ₃ and extracted with ethyl acetate (2 × 25 mL). The combined organic layers were washed with 1 × H ₂ O, 1 × brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. Chromatography on silica gel, eluting with 2: 1 hexane / ethyl acetate, 2,2,2-trifluoro-N- [4-[(4-formylphenyl) oxy] -2-nitro- 0.650 g of 6- (trifluoromethyl) phenyl] acetamide was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) delta ppm 6.63 (br.s, 1H) 7.05 (d, J = 8.79 Hz 2H) 7.57 (d, J = 2.93 Hz, 1 H) 7.89 (d, J = 8.55 Hz , 2H) 8.12 (d, J = 2.93 Hz, 1H) 9.95 (s, 1H).

Step 4 : Preparation of 5-{[4- (1,3-dioxolan-2-yl) phenyl] oxy} -2,7-bis (trifluoromethyl) -1H-benzimidazole

2,2,2-trifluoro-N- [4-[(4-formylphenyl) oxy] -2-nitro-6- (trifluoromethyl) phenyl] acetamide (0.65 g, 1.54 mmol), triethyl orthoformate ( To a mixture of 0.282 mL, 1.69 mmol), and ethylene glycol (0.343 mL, 6.16 mmol) was added (butyl) ₄ NBr ₃ (0.007 g, 0.015 mmol). The reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed with 1xNaHCO _3, 1x brine, then dried (Na ₂ SO _4), filtered and concentrated. The residue was dissolved in ethyl acetate (5 mL) and hydrogenated over 10% palladium on carbon (0.13 g) under a hydrogen atmosphere for 3 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography using a gradient of 20-40% ethyl acetate: hexane to give 5-{[4- (1,3-dioxolan-2-yl) phenyl] oxy} -2,7- Bis (trifluoromethyl) -1H-benzimidazole was obtained. (M + H) 419.1, 2.62 min (LC / MS method A).

Step 5 : Preparation of 4-{[2,4-bis (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} benzaldehyde

  5-{[4- (1,3-Dioxolan-2-yl) phenyl] oxy} -2,7-bis (trifluoromethyl) -1H-benzimidazole (0.260 g, 0.622 mmol) in acetone (2 mL) And MP-TSOH (Argonaut, tosylic acid supported on macroporous polymer, approximately 0.842 g, 1.24 mmol) is stirred for 3 hours, then filtered and concentrated to give the desired 4-{[2,4 -Bis (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} benzaldehyde was obtained and used without further purification.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.08 (d, J = 8.79 Hz, 2H) 7.48 (br.s, 1H) 7.67 (br.s, 1H) 7.89 (d, J = 8.55 Hz, 2H) 9.94 (s, 1H), (M + H) 375.1, 1.05 min (LC / MS method A).

Step 6 : Reductive amination to produce the final compound of General Method 10

4-{[2,4-Bis (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} benzaldehyde (0.103 g, 0.275 mmol), amine (0.302 mmol) in 1 mL of 4% acetic acid methanol solution And then treated with NaCNBH ₃ (0.012 g, 0.192 mmol). The reaction was stirred until the starting aldehyde was consumed and the reaction was diluted with H ₂ O. This mixture was extracted with ethyl acetate. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated. Purification was performed by preparative HPLC, and if desired, the pH of the collected fractions was adjusted to basic with NaHCO ₃ to obtain the free base, and the organics were extracted several times with ethyl acetate. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated.

General method 11: R ^Four Is 4-position F and R ⁶ Is CF _Three And A is CH ₂ Preparation of a benzimidazole compound

Step 1 : Preparation of 3,5-difluoro-2-nitroaniline

While stirring a solution of 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) at 0 ° C., a solution of 7N ammonia in methanol (23 mL) was added. When the reaction solution turned deep red, it was stirred overnight in a sealed tube. The mixture was filtered to remove NH ₄ F and the solvent removed to give a red-orange solid, which was purified by silica gel chromatography using 2: 1 hexane / ethyl acetate to give 6.27 g of 3,5- Difluoro-2-nitroaniline was obtained. (M + H) 175.1, 1.89 min (LC / MS method A).

Step 2 : Preparation of 4-[(3-amino-5-fluoro-4-nitrophenyl) oxy] benzaldehyde

Of 3,5-difluoro-2-nitroaniline (0.400 g, 2.30 mmol), Cs ₂ CO ₃ (1.87 g, 5.74 mmol), and 4-hydroxybenzaldehyde (0.309 g, 2.53 mmol) in dimethyl sulfoxide (5 mL). The solution was heated at 80 ° C. for 2 hours and then cooled. Water was added and the organics were extracted with ethyl acetate (2 × 50 mL). The combined organic layer was washed once with brine and the combined organic layer was washed once with brine and dried (Na ₂ SO ₄ ), filtered and concentrated. Chromatography on silica gel eluting with a gradient of 20% to 60% ethyl acetate / hexanes gave 0.536 g of 4-[(3-amino-5-fluoro-4-nitrophenyl) oxy] benzaldehyde as a yellow solid Got as. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.84 (d, J = 8.55 Hz, 1 H) 6.97 (d, J = 8.79 Hz, 2 H) 7.30 (d, J = 8.55 Hz, 1 H) 7.80 ( dd, J = 8.79 Hz, 2 H) 8.85 (br.s, 1H) 9.82 (s, 1H).

Step 3 : Preparation of 2,2,2-trifluoro-N- {3-fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} acetamide

A solution of 4-[(3-amino-5-fluoro-4-nitrophenyl) oxy] benzaldehyde (1.08 g, 3.91 mmol) in a 1: 1 mixture of trifluoroacetic anhydride / CH ₂ Cl ₂ (10 mL total) Was stirred at ambient temperature for 4 hours and then poured into cold saturated NaHCO ₃ . The organics were extracted with ₂ × 25 mL ethyl acetate and the combined organic layers were washed with 1 × H ₂ O, 1 × brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. The product was eluted by chromatography on silica with 2: 1 hexane / ethyl acetate and 1.27 g 2,2,2-trifluoro-N- {3-fluoro-5-[(4-formylphenyl) oxy ] -2-Nitrophenyl} acetamide was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.66 (dd, J = 8.55, 2.69 Hz, 1 H) 7.19 (d, J = 8.55 Hz, 2 H) 7.96 (d, J = 8.79 Hz, 1 H) 8.10 (dd, J = 9.77, 2.69 Hz, 2 H) 9.97 (br.s, 1H) 10.0 (s, 1H), (M + Na) 395.2, 2.37 min (LC / MS method A)
Step 4: Preparation of 4-{[4-Fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} benzaldehyde

2,2,2-trifluoro-N- {3-fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} acetamide (1.25 g, 3.36 mmol), triethyl orthoformate (0.614 mL, 3.69) mmol), and to a mixture of ethylene glycol (0.749 g, 13.43 mmol) was added Bu ₄ NBr ₃ (0.016 g, 0.034 mmol). The homogeneous reaction was stirred at ambient temperature for 1 hour and then diluted with ethyl acetate. The organics were washed with 1 x NaHCO ₃ , once with brine then it was dried (Na ₂ SO ₄ ), filtered and concentrated, requiring no further purification. The residue (0.400 g) was redissolved in ethyl acetate (5 mL) and hydrogenated with 10% palladium on carbon (0.080 g) under a hydrogen atmosphere for 16 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated. The residue was redissolved in acetone and MP-Fosic acid resin (1.26 g, 1.92 mmol) was added. The mixture was stirred for 16 hours, filtered and the filtrate was concentrated. 0.153 g of 4-{[4-fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} eluting the product with chromatography on silica using 40% ethyl acetate / hexane Benzaldehyde was obtained as an off-white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 6.68 (dd, J = 9.55, 2.69 Hz, 1 H) 7.06 (dd, J = 8.57, 2.95 Hz, 1H) 7.21 (d, J = 8.55 Hz, 2 H ) 7.90 (m, 3 H) 9.96 (s, 1H), (M + H) 325.1, 2.46 min (LC / MS method A).

Step 5: Reductive amination to produce the final compound of General Method 11

4-{[4-Fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} benzaldehyde (0.075 g, 0.231 mmol) in 1.5 mL of 4% acetic acid methanol to amine (0.278 mmol) Followed by treatment with sodium cyanoborohydride (0.010 g, 0.162 mmol). The reaction was stirred and the reaction was diluted with H ₂ O until the starting aldehyde was consumed. This mixture was extracted with ethyl acetate. The organic layers were combined and dried (Na ₂ SO ₄ ), filtered and concentrated. Purification was performed by preparative HPLC and, if desired, the pH of the collected fractions was adjusted to basic with NaHCO ₃ and the organic layer was extracted several times with ethyl acetate. The combined organic layers were then dried (Na ₂ SO ₄ ), filtered and concentrated.

General method 12: R ^Four Is 4-position F and A is CH ₂ Preparation of a benzimidazole compound

Step 1: Preparation of 3,5-difluoro-2-nitroaniline

  While stirring a solution of 1,3,5-trifluoro-2-nitrobenzene (7.08 g, 39.98 mmol) in tetrahydrofuran (50 mL) at 0 ° C., a solution of 7N ammonia in methanol (23 mL) was added. The reaction mixture was stirred overnight in a sealed tube. The mixture was filtered and the solvent removed to give a red-orange solid, which was purified by silica gel column chromatography with 2: 1 hexane / ethyl acetate and 6.27 g of 3,5-difluoro-2-nitro. Obtained aniline. (M + H) 175.1, 1.89 min (LC / MS method A).

Step 2: Preparation of {3-Fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} formamide

A solution of 3,5-difluoro-2-nitroaniline (0.348 g, 2.0 mmol), Cs ₂ CO ₃ (1.63 g, 5 mmol), and 4-hydroxybenzaldehyde (0.268 g, 2.2 mmol) in dimethyl sulfoxide (2 mL) Was heated to 80 ° C. for 1 hour and then cooled. Water was added and the organics were extracted with ethyl acetate (2x50 mL). The combined organic layers were then washed once with brine and dried (Na ₂ SO ₄ ), filtered and concentrated. The product was eluted by chromatography on silica gel (gradient from 20% to 60% ethyl acetate / hexane) and the fractions were concentrated. The conversion of aniline was observed by TLC (˜1.5 h) and the residue was refluxed in 96% formic acid (4 mL) until the reaction was complete, then cooled and poured into ice water. The organics were extracted with ethyl acetate (2 × 25 mL) and the combined organics were washed once with water, once with brine, dried (Na ₂ SO ₄ ), filtered and concentrated to 0.230 g of {3- Fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} formamide was obtained as a solid. (M + H) 305.1, 2.15 minutes (LC / MS method A)
Step 3: Reductive amination of the amine followed by reduction and ring closure to produce the final benzimidazole compound of General Method 12

Treat 3-fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} formamide (0.110 g, 0.362 mmol) with amine (0.434 mmol) in 2.0 mL of 4% acetic acid in methanol. And then treated with sodium cyanoborohydride (0.016 g, 0.253 mmol). The reaction was stirred until the starting aldehyde was consumed and the reaction was diluted with water. This mixture was extracted with ethyl acetate. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated. Purification was performed by chromatography on silica, the desired material was eluted with ethyl acetate, and the fractions were concentrated. The residue was dissolved in ethyl acetate. Triethylamine (1 mol equivalent) was added with 10% palladium on carbon (50% water, 0.030 g) and the reaction mixture was hydrogenated under a hydrogen atmosphere for 6 hours. The reaction mixture was filtered through celite to remove the catalyst and concentrated. The residue was transferred into glacial acetic acid (1 mL) and heated to 60 ° C. to effect ring closure to benzimidazole. Purification of the final product was performed by preparative HPLC, and if desired, the free base was obtained by adjusting the pH of the collected fractions to basic with NaHCO ₃ and the organics were ethyl acetate. And extracted several times. The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated.

General method 13: R ^Four Is 5-CF _Three Preparation of benzimidazole compound

Representative Example: (4,4-Dimethylcyclohexyl) [(4-{[5- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] amine = trifluoroacetate (Example No. 94)
Step 1: Preparation of 4-{[5-amino-4-nitro-2- (trifluoromethyl) phenyl] oxy} benzaldehyde

Dimethyl 5-chloro-2-nitro-4- (trifluoromethyl) aniline (0.240 g, 1.00 mmol), potassium t-butoxide (0.135 g, 1.2 mmol), and 4-hydroxybenzaldehyde (0.147 g, 1.2 mmol) A solution in formamide (5 mL) was heated to 80 ° C. for 6 hours and then cooled. Water was added and the organics were extracted with ethyl acetate (2x50 mL). The combined organic layers were washed once with brine and then dried (Na ₂ SO ₄ ), filtered and concentrated. 0.243 g of 4-{[5-amino-4-nitro-2- (trifluoromethyl) phenyl] oxy was eluted by chromatography on silica gel using a gradient of 30% to 40% ethyl acetate / hexane. } Benzaldehyde was obtained as a yellow solid.

(M + H) 327.1, 2.66 min (LC / MS method A).

Step 2: Preparation of 1,1-dimethylethyl = [(4-{[5-amino-4-nitro-2- (trifluoromethyl) phenyl] oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) carbamate

4-{[5-Amino-4-nitro-2- (trifluoromethyl) phenyl] oxy} benzaldehyde (0.167 g, 0.512 mmol) in 4,4-dimethylacetate methanol solution in 4,4-dimethylcyclohexylamine ( 0.078 g, 0.614 mmol) followed by sodium cyanoborohydride (0.023 g, 0.358 mmol). The reaction was monitored by TLC and stirred until the starting aldehyde was consumed, then the reaction was diluted with water. The mixture was extracted with ethyl acetate and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated. 2: 1 of crude [(4-{[5-amino-4-nitro-2- (trifluoromethyl) phenyl] oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) amine (0.197 g, 0.450 mmol) To a solution in an ethyl acetate / saturated NaHCO ₃ (total 3 mL) mixture was added di-tert-butyl dicarbonate (0.108 g, 0.495 mmol) with stirring. The reaction mixture was stirred for 6 hours at ambient temperature and the layers were separated. The aqueous layer was extracted with 1 × 10 mL ethyl acetate and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to 1,1-dimethylethyl = [(4-{[5-amino-4 -Nitro-2- (trifluoromethyl) phenyl] oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) carbamate was obtained.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.86 (s, 3H) 0.88 (s, 3H) 1.29-1.60 (m, 17H) 3.50-4.00 (m, 1H) 4.33-4.49 (m, 2H) 5.98 ( s, 1H) 6.28 (br.s, 2H) 7.05 (d, J = 8.55 Hz, 1H) 7.31 (d, J = 8.55 Hz, 2 H) 8.49 (s, 1H).

Step 3: (4,4-Dimethylcyclohexyl) [(4-{[5- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] amine = trifluoroacetate (Example No. 94 )

1,1-dimethylethyl = [(4-{[5-amino-4-nitro-2- (trifluoromethyl) phenyl] oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) carbamate (0.427 mmol) The ethyl acetate solution was hydrogenated with 10% palladium on carbon (50% H ₂ O, 0.050 g) under a hydrogen atmosphere for 3 hours. The catalyst was removed by filtration through celite and the filtrate was concentrated. The residue was transferred into a 1: 1 mixture of triethyl orthoformate and acetic acid (total 2 mL) and refluxed for 16 hours, then cooled and concentrated to crude 1,1-dimethylethyl = (4,4-dimethylcyclohexyl) [ (4-{[5- (Trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] carbamate was obtained and used without further purification.

(M + H) 518.2, 3.36 min (LC / MS method A).

The residue was dissolved in ethyl acetate and cooled to -70 ° C. HCl gas was bubbled through the solution to saturate the solution and the reaction mixture was gradually warmed to room temperature. After 1 hour, the reaction mixture was concentrated to give a white solid, then free basified with saturated NaHCO ₃ and extracted with 2 × 10 mL ethyl acetate, dried (Na ₂ SO ₄ ), filtered and concentrated. Purification of the final compound was performed by preparative HPLC and, if desired, the pH of the collected fractions was adjusted to basic with NaHCO ₃ to obtain the free base and the organics were acetic acid several times. Extracted with ethyl. The combined organic layers were then dried (Na ₂ SO ₄ ), filtered and concentrated.

General method 14: R ^Four Of a benzimidazole compound wherein is either Cl or F in the 5-position

Representative Example: N-({4-[(5-Fluoro-1H-benzimidazol-6-yl) oxy] phenyl} methyl) -4,4-dimethylcyclohexaneamine = trifluoroacetate (Example No. 96)
Step 1 : Preparation of 4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] benzaldehyde

5-chloro-4-fluoro-2-nitroaniline (0.380 g, 1.99 mmol), potassium t-butoxide (0.269 g, 2.39 mmol), and 4-hydroxybenzaldehyde (0.292 g, 2.39 mmol) in dimethylformamide (5 mL) ) Was heated at 80 ° C. for 6 hours and then cooled. Water was added and the organics were extracted with ethyl acetate (2x50 mL). The combined organic layers were then washed once with brine and then dried (Na ₂ SO ₄ ), filtered and concentrated. Chromatography on silica gel eluting the product with a gradient of 20% to 30% ethyl acetate / hexanes gave 0.468 g of 4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] benzaldehyde orange As a solid.

¹ H NMR (400 MHz, dimethyl sulfoxide-d ₆ ) δ ppm 6.63 (d, J = 7.57 Hz, 1H) 7.37 (d, J = 8.55 Hz, 2H) 7.45 (br.s, 2H) 7.95-8.01 (m , 3 H) 9.98 (s, 1H).

Step 2 : 1,1-dimethylethyl = ({4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate

4-[(5-Amino-2-fluoro-4-nitrophenyl) oxy] benzaldehyde (0.100 g, 0.362 mmol) in 2.0 mL 4% methanol in acetic acid was added to 4,4-dimethylcyclohexylamine (0.055 g, 0.434). mmol) followed by sodium cyanoborohydride (0.016 g, 0.253 mmol). The reaction was stirred until the starting aldehyde was consumed and the reaction was diluted with water. This mixture was extracted with ethyl acetate. The organic layers were combined, dried (Na ₂ SO ₄ ), filtered and concentrated. To a solution of this crude amine in ethyl acetate / saturated NaHCO ₃ (3 mL total) in a 2: 1 mixture, di-tert-butyl dicarbonate (0.434 mmol) solution was added with stirring. The reaction mixture was stirred for 6 hours at ambient temperature and the layers were separated. The aqueous layer was extracted with 1 × 10 mL ethyl acetate and the combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to 1,1-dimethylethyl = ({4-[(5-amino-2 -Fluoro-4-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate was obtained, which did not require further purification.

(M + H) 488.2, 3.36 min (LC / MS method A).

Step 3 : Preparation of N-({4-[(5-fluoro-1H-benzimidazol-6-yl) oxy] phenyl} methyl) -4,4-dimethylcyclohexaneamine = trifluoroacetate (Example No. 96)

1,1-dimethylethyl = ({4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate (0.158 g, 0.313 mmol) CH _To a solution in ₂ Cl ₂ (3 mL) was added formic anhydride (1.5 mL) [prepared as described in Organic Process and Development, 4 (6), p. 569] at 0 ° C. with stirring. The reaction mixture was stirred for an additional hour at ambient temperature, then concentrated and used without further purification. Crude 1,1-dimethylethyl = (4,4-dimethylcyclohexyl) [(4-{[2-fluoro-5- (formylamino) -4-nitrophenyl] oxy} phenyl) methyl] carbamate (0.173 g, 0.335 mmol) in ethanol (3 mL) and acetic acid (3 mL) was hydrogenated using 10% palladium on carbon (50% H ₂ O, 0.040 g) under a hydrogen atmosphere (*). After 3 hours, the reaction mixture was filtered through celite and the filtrate was concentrated. The residue was free basified with 1N NaOH and extracted with (2 × 10 mL) CH ₂ Cl ₂ . The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was trifluoroacetic acid deprotected with 1 mL trifluoroacetic acid in CH ₂ Cl ₂ (2 mL) and concentrated after 1 h. The final compound was purified by preparative HPLC and N-({4-[(5-fluoro-1H-benzimidazol-6-yl) oxy] phenyl} methyl) -4,4-dimethylcyclohexaneamine = trifluoro Acetate was obtained (Example No. 96).

(*) Example No. 97, N-({4-[(5-fluoro-1H-benzimidazol-6yl) oxy] phenyl} methyl) -2,3-dihydro-1H-inden-2-amine = trifluoro For acetate, hydrogenation and ring closure were performed in two ways. Initially performed as described above, and subsequent preparations were performed as follows. Hydrogenation can be carried out in ethanol as the only solvent. The next ring closure was performed by Limin Wang and collaborators as described in Synth. Commun. 34 (23) 4265-72. Dianiline (1 mmol) trimethyl orthoformate (1.2 mmol) and Yb (OTf) ₃ (0.005 mmol) It can be implemented by the processing according to.

General method 15: R ^Four Is in the 5-position and R ⁶ = CF _Three And A = CH ₂ Preparation of a benzimidazole compound

Representative Example : N-[(4-{[5-Fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] -2,3-dihydro-1H-indene- 2-Amine = trifluoroacetate (Example No. 100)
Step 1 : Preparation of 2,2,2-trifluoro-N- {4-fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} acetamide

4-[(5-Amino-2-fluoro-4-nitrophenyl) oxy] benzaldehyde (synthesis as described previously in General Method 14 Step 1) (0.275 g, 0.996 mmol) and N, N-diisopropylethylamine (0.208 A solution of mL, 1.19 mmol) in CH ₂ Cl ₂ (2 mL) was stirred for 2 h, then water (5 mL) was added. The layers were separated and the aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with (1 × 10 mL) 10% HCl, (1 × 10 mL) NaHCO ₃ , once with brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to 2,2,2-trifluoro-N. -{4-Fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} acetamide was obtained. No further purification was necessary.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.23 (d, J = 8.55 Hz, 2 H) 7.99 (d, J = 8.79 Hz, 2 H) 8.23 (d, J = 10.25 Hz, 1 H) 8.49 ( d, J = 7.32 Hz, 1 H) 10.0 (s, 1H) 11.48 (br.s, 1H), (M + H) 373.1, 2.58 min (LC / MS method A).

Step 2 : Preparation of ({4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-ylamine

2,2,2-Trifluoro-N- {4-fluoro-5-[(4-formylphenyl) oxy] -2-nitrophenyl} acetamide (0.300 g, 0.806 mmol) in CH ₂ Cl ₂ (3 mL) A solution of 2-aminoindane (0.161 g, 1.21 mmol), and acetic acid (0.5 mL) was stirred for 30 minutes, then Na (OAc) ₃ BH (0.205 g, 0.967 mmol) was added slowly over 2 minutes. The reaction mixture was stirred for 1 h at ambient temperature and then H ₂ O (3 mL) was added. The layers were separated and the aqueous layer was extracted with CH ₂ Cl _{2 for an} additional hour. The combined organic layers were washed with 1 × brine, then dried (Na ₂ SO ₄ ), filtered and concentrated ({4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] phenyl} Methyl) 2,3-dihydro-1H-inden-2-ylamine was obtained. No further purification was necessary.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 2.92-2.97 (m, 2H) 3.22-3.27 (m, 2H) 3.72-3.83 (m, 1H) 3.94 (s, 2H) 6.00 (d, J = 7.32 Hz , 1 H) 6.22 (br.s, 2H) 7.07-7.09 (m, 2 H) 7.14-7.21 (m, 4H) 7.44 (d, J = 8.3 Hz, 2 H) 7.92 (d, J = 11.23 Hz, 1 H), (M + H) 394.2, 1.88 min (LC / MS method A)
Step 3 : N-[(4-{[5-Fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] -2,3-dihydro-1H-indene-2 -Amine = trifluoroacetate (Example No. 100)

({4-[(5-amino-2-fluoro-4-nitrophenyl) oxy] phenyl} methyl) 2,3-dihydro-1H-inden-2-ylamine (0.272 g, 0.691 mmol) in tetrahydrofuran (3 mL) And to a solution in saturated NaHCO ₃ (1 mL) was added di-tert-butyl dicarbonate (0.158 g, 0.726 mmol) in one portion. The reaction mixture was stirred for 2 hours and the layers were separated. The aqueous layer was extracted with (1 × 5 mL) diethyl ether and the combined organic layers were washed with 1 × brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was dissolved in CH ₂ Cl ₂ (3 mL) and N, N-diisopropylethylamine (0.145 mL, 0.830 mmol) was added followed by trifluoroacetic anhydride (0.100 mL, 0.726 mmol). The reaction mixture was stirred for 2 hours and H ₂ O (4 mL) was added. The layers were separated and the aqueous layer was extracted with 1 × 5 mL CH ₂ Cl ₂ and the combined organic layers were washed with 1 × brine, then dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl {[4-({2-fluoro-4-nitro-5-[(trifluoroacetyl) amino] phenyl} oxy) Phenyl] methyl} carbamate was used without further purification. (M + H) 590.6, 3.21 min (LC / MS method A).

Crude 1,1-dimethylethyl = 2,3-dihydro-1H-inden-2-yl {[4-({2-fluoro-4-nitro-5-[(trifluoroacetyl) amino] phenyl} oxy) phenyl ] To a solution of methyl} carbamate (0.375 g, 0.636 mmol) in ethanol (3 mL) was added 10% palladium on carbon (0.076 g) and the reaction mixture was hydrogenated under a hydrogen atmosphere. The reaction mixture was stirred for 4 hours and the catalyst was removed by filtration through celite. The filtrate was concentrated and the residue was redissolved in glacial acetic acid (3 mL) and heated to 60 ° C. for 1 h, cooled, concentrated and azeotroped several times with toluene / CH ₂ Cl ₂ . The residue was dissolved in CH ₂ Cl ₂ and trifluoroacetic acid was added. The reaction mixture was stirred for 16 hours and then concentrated. The final compound was purified by preparative HPLC to give N-[(4-{[5-fluoro-2- (trifluoromethyl) -1H-benzimidazol-6-yl] oxy} phenyl) methyl] -2, 3-Dihydro-1H-indene-2-amine = trifluoroacetate (Example No. 100) was obtained.

General method 16: A is CH ₂ And Y is CR ⁶ Preparation of 2-position substituted benzimidazole compounds

Step 1: Preparation of 4-[(4-amino-3-nitrophenyl) oxy] benzaldehyde

A mixture of 4-amino-3-nitrophenol (1.54 g; 10.0 mmol), 4-fluorobenzaldehyde (1.05 mL; 10.0 mmol) and Cs ₂ CO ₃ (3.91 g; 12.0 mmol) in anhydrous dimethyl sulfoxide (10 mL). Heated at 80 ° C. under nitrogen. After 1 hour, an additional portion of 4-fluorobenzaldehyde (0.050 mL; 0.50 mmol) was added and heating was continued. After 2 hours the mixture was cooled, poured into water and extracted three times with ethyl acetate. The combined organic layers were washed (H ₂ O, brine), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate / hexane) to give 2.56 g of 4-[(4-amino-3-nitrophenyl) oxy] benzaldehyde as an orange solid. 1H NMR (400 MHz, CDCl ₃ ) δ ppm 6.11 (br.s, 2H), 6.90 (d, J = 9.1 Hz, 1H), 7.04 (m, 2H), 7.20 (dd, J = 9.0, 2.8 Hz, 1H), 7.86 (m, 2H), 7.89 (d, J = 2.7 Hz, 1H), 9.93 (s, 1H) ppm, (M + H) 259, 2.33 min (LC / MS method A).

Step 2: Preparation of 1,1-dimethylethyl = ({4-[(4-amino-3-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate

Of 4,4-dimethylcyclohexylamine hydrochloride (0.911 g; 5.56 mmol), 4-[(4-amino-3-nitrophenyl) oxy] benzaldehyde (1.304 g; 5.05 mmol) and triethylamine (0.77 mL; 5.5 mmol) To a solution in methanol (50 mL) was added NaBH ₃ CN (0.317 g; 5.05 mmol) in one portion at room temperature. The mixture was stirred for 16 hours at room temperature and an additional portion of 4,4-dimethylcyclohexylamine hydrochloride (0.083 g; 0.51 mmol), triethylamine (0.08 mL; 0.6 mmol) and NaBH ₃ CN (0.035 g; 0.56 mmol). Was added. Stirring was continued for 6 hours and volatiles were removed in vacuo. The residue was dissolved in CH ₂ Cl ₂ (25 mL) and triethylamine (0.70 mL; 5.1 mmol) and di-tert-butyl dicarbonate (1.10 g; 5.05 mmol) were added. The mixture was stirred for 14 hours at room temperature, concentrated on a minimum amount of silica gel and purified by silica gel flash chromatography (ethyl acetate / hexane) to give 1.62 g of 1,1-dimethylethyl = ({4-[( 4-Amino-3-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate was obtained as an orange foam.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.86 (s, 3H), 0.88 (s, 3H), 1.14-1.71 (br.overlapping m, 17 H), 3.97 (br s, 1H), 4.35 (br s, 2H), 5.98 (br.s, 2H), 6.82 (d, J = 9 Hz, 1H), 6.90 (m, 2H), 7.17 (dd, J = 9.0, 2.8 Hz, 1H), 7.21 ( m, 2H, partially overlapping 7.17), 7.73 (partially divided d, J ≒ 2.3 Hz, 1H) ppm, (M + Na) 492, 3.35 min (LC / MS method A).

Step 3: Acyl of 1,1-dimethylethyl ({4-[(4-amino-3-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate to produce nitroanilide intermediate Conversion

Representative example: 1,1-dimethylethyl = [(4-{[4- (acetylamino) -3-nitrophenyl] oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) carbamate (R = CH ₃ )
1,1-dimethylethyl = ({4-[(4-amino-3-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate (0.115 g; 0.244 mmol) and triethylamine (0.040 mL; To a solution of 0.27 mmol) in CH ₂ Cl ₂ (2.5 mL) was added acetyl chloride (0.020 mL; 0.27 mmol) and the mixture was stirred at room temperature. After 16 hours, an additional portion of acetyl chloride (0.010 mL) and 4- (dimethylamino) pyridine (3 mg) were added and stirring was continued for another 2 hours. The whole is concentrated onto a small amount of silica gel and purified by silica gel flash chromatography (ethyl acetate / hexane) to give 0.103 g of 1-dimethylethyl = [(4-{[4- (acetylamino) -3-nitrophenyl. ] Oxy} phenyl) methyl] (4,4-dimethylcyclohexyl) carbamate was obtained as a yellow gum.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 0.87 (s, 3H), 0.89 (s, 3H), 1.14-1.74 (br.overlapping m, 17 H), 3.40-4.09 (br.m, 1H) , 4.37 (br. S, 2H), 6.96 (m, 2H), 7.27 (br.m, 2H, overlapping with solvent), 7.32 (dd, J = 9.3, 2.9 Hz, 1H), 7.74 (d, J = 2.9 Hz, 1H), 8.69 (d, J = 9.3 Hz, 1H), 10.12 (br. S, 1H). (MH) 510, 3.20 min (LC / MS method A).

Other nitroanilide intermediates were prepared as follows:
1,1-dimethylethyl = ({4-[(4-amino-3-nitrophenyl) oxy] phenyl} methyl) (4,4-dimethylcyclohexyl) carbamate (0.125 g; 0.267 mmol) in tetrahydrofuran (2 mL) To this solution was added pyridine (mL; 0.53 mmol) and acylating agent (acid chloride or anhydride; 0.40 mmol) at room temperature. The mixture was heated at 70 ° C. (a septum sealed vial) overnight. The mixture was cooled, diluted with ethyl acetate, washed separately (using H ₂ O, saturated Na ₂ CO ₃ , brine), dried over Na ₂ SO ₄ , concentrated and flash chromatographed (ethyl acetate / Hexane) to give a nitroanilide intermediate. The following nitroanilide intermediates were prepared in this manner:
1,1-dimethylethyl = (4,4-dimethylcyclohexyl) [(4-{[3-nitro-4- (propanoylamino) phenyl] oxy} phenyl) methyl] carbamate (R = Et), (MH) 524, 3.27 min (LC / MS method A).

1,1-dimethylethyl = (4,4-dimethylcyclohexyl) {[4-({3-nitro-4-[(trifluoroacetyl) amino] phenyl} oxy) phenyl] methyl} carbamate (R = CF ₃ ) , (MH) 564, 3.30 min (LC / MS method A).

1,1-dimethylethyl = (4,4-dimethylcyclohexyl) {[4-({3-nitro-4-[(phenylcarbonyl) amino] phenyl} oxy) phenyl] methyl} carbamate (R = Ph), ( MH) 572, 3.42 min (LC / MS method A).

Step 4: Nitro group reduction and ring closure to produce 2-position substituted benzimidazoles

To a solution of the nitroanilide intermediate in ethyl acetate (5 mL) was added Pd-carbon (10 wt% (dry basis), wet, degussa type E101; about 0.10 equivalent Pd) and the slurry was added to a Parr hydrogenator (50 psi H ₂ ) was used to hydrogenate until complete reduction of the starting material was observed (as judged by LC-MS). The catalyst was removed by filtration (either Celite® pad or 0.45 μm PTFE membrane filter), the filtrate was concentrated and the residue was dissolved in acetic acid (2-3 mL). The resulting solution was heated at 65 ° C. until complete conversion of the anilino-anilide intermediate to benzimidazole was observed (as judged by LCMS). The mixture is concentrated in vacuo, redissolved in toluene and concentrated in vacuo to give a benzimidazole substituted in the 2-position, which is carried directly on to the next step 5, or If necessary, purified by chromatography. Benzimidazoles substituted in the 2-position prepared in this manner were as follows:
1,1-dimethylethyl = (4,4-dimethylcyclohexyl) ({4-[(2-methyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) carbamate (R = CH ₃ ) Used directly in step 5 without purification), (M + H) 464, 2.55 min (LC / MS method A).

1,1-dimethylethyl = (4,4-dimethylcyclohexyl) ({4-[(2-ethyl-1H-benzoimidazol-5-yl) oxy] phenyl} methyl) carbamate (R = Et) Purified by RP-HPLC ( _C18 column, MeCN / H ₂ O / 0.1% TFA) and then treated in step 5), (M + H) 478, 2.59 min (LC / MS method A).

1,1-dimethylethyl = (4,4-dimethylcyclohexyl) [(4-{[2- (trifluoromethyl) -1H-benzimidazol-5-yl] oxy} phenyl) methyl] carbamate (R = CF ₃ ) (Used directly in step 5 without purification), (MH) 516, 3.29 min (LC / MS method A).

1,1-dimethylethyl = (4,4-dimethylcyclohexyl) ({4-[(2-phenyl-1H-benzimidazol-5-yl) oxy] phenyl} methyl) carbamate (R = Ph) (flash chromatography ( (Ethyl acetate / hexane) and then treated in step 5), (M + H) 526, 3.12 min (LC / MS method A).

Step 5: Removal of the tert-butoxycarbonyl protecting group to produce the final compound of Formula 1

To a solution of the tert-butoxycarbonyl protected intermediate (step 4 above) and (ethyl) ₃ SiH (≧ 2.5 eq) in CH ₂ Cl ₂ (5 mL) was added TFA (1 mL) in one portion. The mixture was stirred for 1 hour at room temperature and concentrated in vacuo to give the pure final compound (as TFA salt).

Further amine preparation:
Preparation of 4,4-dimethylcyclohexylamine hydrochloride:
Prepared similarly to the procedures of Thomas P. Johnston, George S. McCaleb, Pamela S. Opliger, W. Russelll Laster and John A. Montgomery. J. Med. Chem., 14 (7), 600-614, 1971.

Step 1 : 4,4-Dimethylcyclohexanone
4,4-Dimethyl-2-cyclohexen-1-one [Aldrich] (5.5 g) was dissolved in 50 ml of ethyl acetate. The solution was hydrogenated with 0.25 g of 10% palladium on carbon (Degusa E101) for 3 hours at room temperature under 15 psi pressure. The mixture was passed through a Celite® pad to remove the catalyst and then concentrated to dryness in vacuo. The desired 4,4-dimethylcyclohexanone was obtained as a colorless solid (5.56 g). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.07 (s, 6H), 1.65 (t, J = 7 Hz, 4H), 2.35 (t, J = 7 Hz, 4H).

Step 2 : 4,4-dimethylcyclohexanone oxime
To a solution of 4,4-dimethylcyclohexanone (3.0 g, 0.024 mole) and hydroxylamine hydrochloride (2.2 g, 0.031 mole) in a mixture of ethanol (15 mL) and water (20 mL) was added sodium carbonate (3.3 g) at room temperature. , 0.031 mole) in water (10 mL) was added dropwise. The mixture was heated at reflux for 3 hours, cooled to room temperature and concentrated in vacuo to remove ethanol. The aqueous residue was extracted several times with ethyl acetate. The organic extract was dried (MgSO ₄ ), filtered and concentrated in vacuo to give 3.0 g (88%) of the desired 4,4-dimethylcyclohexanone oxime as a white solid. This was used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.93 (s, 6H), 1.28 (t, J = 6.6 Hz, 2H), 1.35 (t, J = 6.6 Hz, 2H), 2.11 (t, J = 6.6 Hz, 2H), 2.36 (t, J = 6.6 Hz, 2H), 10.12 (s, 1H)).

Step 3 : 4,4-Dimethylcyclohexylamine hydrochloride
A mixture of 4,4-dimethylcyclohexanone oxime (3.0 g, 0.021 mole) and Raney 2800 Nickel (0.8 g, water slurry) in ethanol (100 mL) was hydrogenated at 50 psi in a Parr hydrogenator. After the hydrogen absorption ceased, the mixture was filtered through Celite®. 50 mL of diethyl ether containing 1N HCl was added to the filtrate. The mixture was concentrated in vacuo. The residue is triturated with diethyl ether, filtered, washed with diethyl ether and air dried to give 2.60 g (76%) of the desired 4,4-dimethylcyclohexylamine hydrochloride as a white solid. It was.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.86 (s, 3H), 0.87 (s, 3H), 1.19 (m, 2H), 1.36 (m, 2H), 1.48 (m, 2H), 1.70 (m, 2H), 2.87 (m, 1H), 7.93 (br. s, 3H).

Synthesis of 5,6-difluoro-2,3-dihydro-1H-inden-2-amine hydrochloride
Step 1: Preparation of 3- (3,4-difluorophenyl) propanoyl chloride

  To a dichloromethane solution (200 mL) containing 3,4-difluorophenylpropionic acid (30.45 g, 163.6 mmol) and 2 drops of dimethylformamide was added oxalyl chloride (41.4 g, 327.1 mmol) over 20 minutes. The resulting solution was stirred for 24 hours, at which point the solvent was removed in vacuo. The residual oil was then evaporated with toluene (approximately 100 mL) to give 33.4 g of 3- (3,4-difluorophenyl) propanoyl chloride as a yellow liquid, which was used directly in the next step.

Step 2: 5,6-Difluoro-2,3-dihydro-1H-inden-1-one

Carbon disulfide solution containing 3- (3,4-difluorophenyl) propanoyl chloride (33.4 g, 163.6 mmol) at 0 ° C in a carbon disulfide solution (300 mL) containing AlCl ₃ (76.4 g, 572.6 mmol) (120 mL) was added over 10 minutes. The solution was stirred for 30 minutes at 0 ° C. and heated at reflux for 4 hours. Upon cooling to room temperature, the solution was carefully poured onto crushed ice. The carbon disulfide layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO ₄ and the solvent removed in vacuo. The residual solid was purified by silica gel column chromatography (5-10% ethyl acetate / hexane) to give 19.3 g (114.9 mmol, 70% yield) of 5,6-difluoro-2,3-dihydro-1H-indene-1- ON was obtained as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.50 (t, 1H, J = 8.0 Hz), 7.24 (t, 1H, J = 6.6 Hz), 3.09 (t, 2H, J = 5.5 Hz), 2.72- 2.69 (m, 2H).

Step 3: 5,6-Difluoro-1H-indene-1,2 (3H) -dione 2-oxime

  Isoamyl nitrite (4.17 g, 35.6 mmol) in methanol solution (90 mL) containing 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4 mmol) at 40 ° C Was added followed by concentrated HCl (2.7 mL). Upon heating for 45 minutes, the solution was cooled to room temperature and water was added. The resulting precipitate was collected via vacuum filtration. The solid was rinsed thoroughly with water to give 3.97 g (20.2 mmol, 74% yield) of 5,6-difluoro-1H-indene-1,2 (3H) -dione 2-oxime as a pale orange solid Obtained. The crude solid was processed directly in the next step.

Step 4: 5,6-difluoro-2,3-dihydro-1H-inden-2-amine hydrochloride

To an acetic acid solution (100 mL) containing 5,6-difluoro-1H-indene-1,2 (3H) -dione 2-oxime (3.97 g, 20.2 mmol) in a Parr bottle was added 8 mL concentrated HCl followed by 10% Pd / C (1.07 g) was added. The solution was hydrogenated on a Parr hydrogenator at 50 psi for 24 hours. The heterogeneous solution was filtered through a celite bed and the celite was thoroughly rinsed with chloroform. The solvent was then removed in vacuo and the remaining dark oil was dissolved in water. The aqueous solution was then basified with solid K ₂ CO ₃ . The organics were extracted 3 times with chloroform and then dried over MgSO ₄ . The solvent was removed in vacuo and the remaining amber oil was purified by column chromatography (10% MeOH / CH ₂ Cl ₂ ) to give 1.06 g (6.26 mmol) 5,6-difluoro-2,3-dihydro-1H -Inden-2-amine was obtained as a brown oil. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.95 (t, 2H, J = 8.9 Hz), 3.83 (m, 1H), 3.10 (dd, 2H, J = 15.8, 6.8 Hz), 2.60 (dd, 2H, J = 15.8 & 5.0 Hz) ppm; (M + 1) 170.1, 0.68 min (LC / MS method A). The oil was dissolved in diethyl ether (approximately 5 mL) and 4.0 mL of 4.0 M HCl dioxane solution (16.0 mmol) was added. The resulting precipitate was triturated with diethyl ether and collected by vacuum filtration to yield 795 mg (3.87 mmol, 19% yield) of 5,6-difluoro-2,3-dihydro-1H-indene-2-amine hydrochloride The salt was obtained as an off-white solid.

Synthesis of 2-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride
Step 1 : 1,1-dimethylethyl = (5-bromo-2,3-dihydro-1H-inden-2-yl) carbamate

(5-Bromo-2,3-dihydro-1H-inden-2-yl) amine hydrobromide (5.61 g; 19.1 mmol; Prashad, M; Hu, B .; Har, D .; Repic, O. Blacklock, T .; Acemoglub, M. Adv. Synth. Catal. 2001, 343 (5), 461) in a slurry of CH ₂ Cl ₂ (40 mL) once with triethylamine (5.8 mL, 42 mmol). Added to. The mixture was stirred for 15 minutes and di-tert-butyl dicarbonate (4.58 g; 21 mmol) was added in one portion. After 2 hours, the reaction mixture was adsorbed onto a minimum amount of silica gel and purified by silica gel flash chromatography (ethyl acetate / hexane) to give 5.94 g of 1,1-dimethylethyl = (5-bromo-2,3- Dihydro-1H-inden-2-yl) carbamate was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.39 (s, 9H), 2.73 (m, 2H), 3.08 (m, 2H), 4.20 (app.sext, J = 7.0 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 7.19 (br.d, J = 6.8 Hz, 1H), 7.30 (partially decomposed dd, J = 8.0, ~ 1.9 Hz, 1H), 7.38 (m, 1H).

Step 2 : 1,1-dimethylethyl = (5-cyano-2,3-dihydro-1H-inden-2-yl) carbamate

1,1-Dimethylethyl = (5-bromo-2,3-dihydro-1H-inden-2-yl) carbamate (3.0 g, 9.26 mmol), diphenylphosphinoferrocene (645 mg, 1.16 mmol) obtained from all steps , Pd ₂ dba ₃ (532 mg, 0.58 mmol), zinc cyanide (1.50 g, 12.8 mmol) and water in 50 mL dimethylformamide were degassed four times under nitrogen and 21 hours at 110 ° C. Stir. Upon cooling, the reaction was quenched with saturated NH ₄ Cl and the organics were transferred into ethyl acetate. The organic layer was washed with water (3x), dried over washed with saturated aqueous NaCl and MgSO _4. The solvent was removed in vacuo and the remaining orange-yellow oil was purified by silica gel column chromatography (15-40% ethyl acetate / hexane) to give 1.85 g (7.18 mmol, 78% yield) of 1,1-dimethylethyl = (5-Cyano-2,3-dihydro-1H-inden-2-yl) carbamate was obtained as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 7.45 (d, 1H, J = 7.9 Hz), 7.28 (d, 1H, J = 7.7 Hz), 4.69 (br.s), 1H ), 4.47 (s (br), 1H), 3.33-3.25 (m, 2H), 2.86-2.80 (m, 2H), 2.79 (s, 9H) ppm. (M + 1) 259.1, 2.46 min (LC / MS method A).

Step 3 : 2-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride

To a dioxane solution (30 mL) containing 1,1-dimethylethyl = (5-cyano-2,3-dihydro-1H-inden-2-yl) carbamate (1.85 g, 7.18 mmol) was added 18 mL of 4.0 M HCl dioxane. Solution (72.0 mmol) was added at room temperature. When the resulting solution was stirred for approximately 18 hours, the heterogeneous solution was diluted with diethyl ether. The solid was collected by vacuum filtration and thoroughly rinsed with diethyl ether to give 1.33 g (6.84 mmol, 95% yield) of 2-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride The salt was obtained as a tan solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.65 (s, 1H), 7.59 (d, 1H, J = 7.9 Hz), 7.46 (d, 1H, J = 7.9 Hz), 4.14 (m, 1H) , 3.51-3.43 (m, 2H), 3.10-3.04 (m, 1H).

Preparation of (2R)-and (2S) -5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride
Step 1 : 5-Fluoro-2,3-dihydro-1H-inden-2-amine

To a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (10.0 g; 66.7 mmol) in methanol at 40 ° C., n-butylnitrile (13.2 mL; 113 mmol) was added dropwise for 3 minutes. Concentrated HCl (10 mL) was then added dropwise at a rate that maintained the internal temperature below 55 ° C. The mixture was stirred for 30 minutes and concentrated in vacuo. The residue was diluted with ethyl acetate and saturated NaHCO ₃ , filtered and the layers were separated. The aqueous layer was extracted with ethyl acetate (x1) and the combined organic layers were washed (H ₂ O, brine), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate / hexane) to give 7.59 g of keto-oxime intermediate as an orange solid. This solid is dissolved in acetic acid / H ₂ SO ₄ (250 mL / 12.5 mL), Pd-carbon (4.5 g; 10 wt% (dry basis), wet, Degussa type E101) is added and the mixture is added to a Parr hydrogenator ( Hydrogenated using 50 psi H ₂ ) for approximately 18 hours. The mixture was filtered through celite (H ₂ O wash) and partially concentrated to give an aqueous mixture. The mixture was adjusted to pH 11 (1N NaOH) and extracted with CHCl ₃ (x5). The combined organics were washed (brine), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 5.79 g of 5-fluoro-2,3-dihydro-1H-inden-2-amine amber Was obtained and used without further purification. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.69 (br.s, 2H), 2.53 (m, 2H, overlapping solvent), 2.99 (m, 2H), 3.69 (quint, J = 6.2 Hz, 1H), 6.89 (partially resolved ddd, J = 9.8, ~ 7.7, 2.5 Hz, 1H), 6.99 (partially resolved dd, J = 9.3, ~ 2.3 Hz, 1H), 7.16 (partially Decomposed dd, J = 8.3, 5.6 Hz, 1H).

Step 2 : rac- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) benzylcarbamate

To a mixture of 5-fluoro-2,3-dihydro-1H-inden-2-amine (5.79 g; 38.3 mmol; step 1 above) and saturated Na ₂ CO ₃ (200 mL) was added benzyl chloroformate (6.9 mL) at room temperature. 46 mmol) was added. The mixture was stirred for 1 hour at room temperature and extracted with ethyl acetate (x3). The combined organic layers were washed (H ₂ O, brine), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography (ethyl acetate / hexane) to give 8.33 g of rac- (5-fluoro-2,3-dihydro-1H-inden-2-yl) benzylcarbamate as an off-white solid Obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.77 (m, 2H), 3.12 (m, 2H), 4.29 (app.sext, J = 7.1 Hz, 1H), 5.02 (s, 2H), 6.94 (m, 1H), 7.03 (partially decomposed dd, J = 9.2, ~ 2.4 Hz, 1H), 7.19 (partially decomposed dd, J = 8.2, 5.5 Hz, 1 H), 7.28-7.40 ( m, 5H), 7.64 (d, J = 6.8 Hz, 1H).

Step 3 : rac- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) benzylcarbamate [(2S) -5-fluoro-2,3-dihydro-1H-inden-2-yl Resolution of benzyl carbamate and [(2R) -5-fluoro-2,3-dihydro-1H-inden-2-yl] benzyl carbamate
rac- (5-Fluoro-2,3-dihydro-1H-inden-2-yl) benzylcarbamate was purified by supercritical chromatography on an AD-H prep column (30 mm ID x 25 mm, 5 micrometer particle size), methanol / The individual enantiomers were separated using CO ₂ (17/83) at 140 bar, 90 g / min total flow, 33 ° C. Chromatographic peak was detected at 215 nm. The absolute configuration assignments for the enantiomers obtained above are the vibrational circular dichroism (VCD) spectrum (c = 0.036 gm / ml; CDCl ₃ ) and [(2S) -5-fluoro-2, This was done by comparison with the calculated VCD spectrum for 3-dihydro-1H-inden-2-yl] benzylcarbamate. The earlier eluting enantiomer from the above chiral separation was found to have a VCD band with the same relative signature as the (S) -configuration model used for ab initio calculations and was assigned to the (S) -configuration. In contrast, the slower eluting enantiomer was found to have a VCD band of the opposite relative signature to the (S) -configuration model used for ab initio calculations and was assigned to the (R) -configuration.

Step 4 : (S)-and (R) -5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride

Representative Example : (S) -5-Fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride
To a solution of [(2S) -5-fluoro-2,3-dihydro-1H-inden-2-yl] benzylcarbamate (2.26 g; 7.93 mmol) in ethyl acetate / ethanol (40 mL each) was added Pd—C (0.85 g; 10 wt% (dry basis), wet, degussa type E101) was added. The mixture was stirred for 5 hours under an atmosphere of H ₂ and the catalyst was removed by filtration through a 0.45 micrometer PTFE membrane filter. HCl (5 mL of 4N dioxane solution) was added to the filtrate and the whole was concentrated to dryness and 1.41 g of (S) -5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride was tan As a solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.97 (m, 2H), 3.24 (m, 2H), 4.00 (m, 1), 7.01 (m, 1H), 7.13 (partially resolved dd , J = 9.2, ~ 2.4 Hz, 1H), 7.28 (dd, J = 8.4, 5.4 Hz, 1H), 8.40 (br. S, 2H). (M + H) 152, 0.73 min (LC / MS method C).

(R) -5-Fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride This compound was converted to (S) -5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride When prepared in the same manner, it showed identical ¹ H NMR spectra and LC / MS residence times.

Preparation of [5- (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride

  Susanne R. Haadsma-Svensson, Kerry A. Cleek, Dac M. Dinh, J. Neil Duncan, Christopher L. Haber, Rita M. Huff, Mary E. Lajiness, Nanette F. Nichols, Martin W. Smith, Kjell A. Prepared similarly to the procedure of Svensson, Matt J. Zaya, Arvid Carlsson and Chiu-Hong Lin, J. Med. Chem. 44, (26) 4716-4732.

Step 1 : Preparation of (2Z) -5- (methyloxy) -1H-indene-1,2 (3H) -dione 2-oxime

  A solution of 5- (methyloxy) -2,3-dihydro-1H-inden-1-one (1.0 g, 6.2 mmol) in methanol (15 mL) at 40 ° C. with n-butyl nitrite (0.8 mL, 6.25) mmol) was added followed by concentrated HCl (0.6 mL). The reaction was stirred for 30 minutes, during which time a precipitate formed which was collected, dried and used without further purification.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.60 (br.s, 2H) 3.86 (s, 3H) 6.99 (dd, J = 8.54, 2.2 Hz, 1H) 7.12 (d, J = 1.71 Hz, 1H) 7.66 (d, J = 8.55 Hz, 1 H) 12.45 (s, 1H).

Step 2 : Preparation of [5- (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride

(2Z) -5- (Methyloxy) -1H-indene-1,2 (3H) -dione 2-oxime (0.96 g, 5.02 mmol) in glacial acetic acid (25 mL) and concentrated H ₂ SO ₄ (2 mL) To the solution was added 10% palladium on carbon (50% H ₂ O, 0.200 g). The mixture was hydrogenated on a Parr apparatus at 50 psi for 7 hours, then filtered through celite to remove the catalyst and washed with 2 × 10 mL methanol and concentrated to remove acetic acid and basified to pH 12, at which point the solid Was formed and extracted with CH ₂ Cl ₂ ( ₂ × 100 mL). The combined organic layer was dried (Na ₂ SO ₄ ) and concentrated to half volume. HCl gas was bubbled through the remaining solution for approximately 1 minute and the resulting mixture was concentrated and after standing at ambient temperature for 15 minutes, 0.906 g of [5- (methyloxy) -2,3-dihydro-1H-indene -2-yl] amine hydrochloride was obtained.

¹ NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.84-2.98 (m, 2H) 3.09-3.24 (m, 2H) 3.75 (s, 3H) 3.92 (br.s, 1H) 6.73 (dd, J = 8.3 , 2.44 Hz, 1H) 6.83 (d, J = 2.2 Hz, 1H) 7.13 (d, J = 8.06 Hz, 1 H) 8.40 (br.s, 2H).

Preparation of [4- (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride

  This compound is converted to 4- (methyloxy) -2,3-dihydro-1H-indene- in the same manner as [5- (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride. Prepared from 1-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.84-2.98 (m, 2H) 3.10-3.27 (m, 2H) 3.75 (s, 3H) 3.95 (br.s, 1H) 6.79 (d, J = 8.06 Hz, 1H) 6.84 (d, J = 7.32 Hz, 1H) 7.16 (t, J = 7.81 Hz, 1 H) 8.31 (br.s, 2H).

Preparation of [5,6-bis (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride

  This compound was treated with 5,6-bis (methyloxy) -2,3-dihydro-1H- in the same manner as [5- (methyloxy) -2,3-dihydro-1H-inden-2-yl] amine hydrochloride. Prepared from inden-1-one.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.84-2.98 (m, 2H) 3.10-3.27 (m, 2H) 3.75 (s, 3H) 3.95 (br.s, 1H) 6.79 (d, J = 8.06 Hz, 1H) 6.84 (d, J = 7.32 Hz, 1H) 7.16 (t, J = 7.81 Hz, 1 H) 8.31 (br.s, 2H).

Preparation of (2-methyl-2,3-dihydro-1H-inden-2-yl) amine hydrochloride

Step 1 : Preparation of methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate

To a flask cooled to 0 ° C. containing diisopropylamine (2.06 mL, 14.58 mmol) in tetrahydrofuran (14 mL) was added dropwise over 15 minutes to a solution of n-butyllithium (5.55 mL of 2.5 M hexane solution, 14.58 mmol). Was added. The mixture was stirred for 30 minutes. A second flask containing 2-methyl-1-indanone (2.03 g, 13.89 mmol) in tetrahydrofuran (10 mL) was cooled at −78 ° C. under N ₂ . Freshly prepared lithium diisopropylethylamide was cooled to -78 ° C and added dropwise via cannula. The orange mixture becomes somewhat heterogeneous after 30 minutes, so raw methyl cyanoformate (1.32 mL, 16.66 mmol) is then added and the reaction mixture is stirred for an additional 40 minutes, allowing the reaction to warm to −20 ° C. Is done. The reaction was quenched with saturated aqueous NH ₄ Cl and the organics were extracted with 2 × 25 mL diethyl ether, washed once with brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to 2 -Methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate was obtained. No further purification was required.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.52 (s, 3H) 3.00 (d, J = 17.32 Hz, 1 H) 3.67-3.73 (m, 4H) 7.41 (t, J = 7.57 Hz, 1 H) 7.47 (m, 1H) 7.63 (m, 1 H) 7.79 (d, J = 7.57 Hz, 1 H).

Step 2 : Methyl 2 -methyl-2,3-dihydro-1H-indene-2-carboxylate

A solution of methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol) in glacial acetic acid (22 mL) and concentrated H ₂ SO ₄ (2 mL) Hydrogenated in Parr apparatus under 50 psi hydrogen using 10% palladium on carbon (50% H ₂ O, 0.200 g) as catalyst. After 4 hours the reaction was filtered to remove the catalyst and washed with 2x methanol, then concentrated to remove most of the acetic acid. The residue was neutralized with saturated Na ₂ CO ₃ and the organics were extracted twice with 25 mL ethyl acetate, then the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and filtered. Concentration gave 2.0 g of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.35 (s, 3H) 2.81 (d, J = 15.63 Hz, 2 H) 3.47 (d, J = 15.63 Hz, 2 H) 3.71 (s, 3H) 7.12- 7.23 (m, 4H).

Step 3 : 2-Methyl-2,3-dihydro-1H-indene-2-carboxylic acid

Lithium hydroxide monohydrate in a solution of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate (1.80 g, 9.46 mmol) in tetrahydrofuran / H ₂ O / methanol (4 mL / 1 mL / 1 mL) Product (1.19 g, 28.39 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 hours and then the mixture was acidified to pH 3 using 1N HCl. The organics were extracted twice with 25 mL diethyl ether and the combined organic layers were washed with brine, then dried (Na ₂ SO ₄ ), filtered and concentrated to 2-methyl-2,3-dihydro-1H. -Indene-2-carboxylic acid was obtained as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.39 (s, 3H) 2.83 (d, J = 15.87 Hz, 2 H) 3.50 (d, J = 15.87 Hz, 2 H) 7.12-7.23 (m, 4H)
Step 4 : Phenylmethyl = (2-methyl-2,3-dihydro-1H-inden-2-yl) carbamate

To a solution of 2-methyl-2,3-dihydro-1H-indene-2-carboxylic acid (0.200 g, 1.14 mmol) and triethylamine (0.166 mL, 1.19 mmol) in 2 mL of benzene at 0 ° C. with diphenylphosphoryl. Azide (0.257 g, 1.19 mmol) was added. The reaction mixture was stirred for 15 minutes and benzyl alcohol (0.123 mL, 1.19 mmol) was added and the reaction was heated at reflux for 16 hours, then cooled and 10% HCl was added. The organics were extracted with 2x25mL of ethyl acetate, then washed with 1x brine, dried (Na ₂ SO _4), filtered and concentrated. The residue was chromatographed on silica eluting with 5: 1 hexane / ethyl acetate to give 0.271 g of phenylmethyl = (2-methyl-2,3-dihydro-1H-inden-2-yl) carbamate .

¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.55 (s, 3H) 2.98 (d, J = 15.87 Hz, 2 H) 3.28 (d, J = 15.87 Hz, 2 H) 7.12-7.18 (m, 4H) 7.29-7.37 (m, 5H).

Step 5 : (2-Methyl-2,3-dihydro-1H-inden-2-yl) amine hydrochloride

Phenylmethyl = (2-methyl-2,3-dihydro-1H-inden-2-yl) carbamate (0.271 g, 0.963 mmol) and 10% palladium on carbon (50% H ₂ O, 0.050 g) in ethanol (2 mL ) The Parr container contained therein was filled and evacuated several times with hydrogen and then shaken for 4 hours while maintaining a final pressure of 40 psi. The catalyst was removed by filtration through Celite® and the filtrate was concentrated to give an oil. The residue was dissolved in ethyl acetate, cooled to −70 ° C., and HCl gas was bubbled through the solution to saturate. The reaction mixture was stirred for 1 hour and then concentrated to give 0.175 g of (2-methyl-2,3-dihydro-1H-inden-2-yl) amine hydrochloride as a white solid.

¹ H NMR (400 MHz, methanol-d ₄ ) δ ppm 1.56 (s, 3H) 3.17 (br.s, 4H) 7.19-7.29 (m, 4H).

Preparation of 3,3-dimethylcyclohexylamine hydrochloride
Step 1 : 3,3-dimethylcyclohexanone oxime

To a mixture of 3,3-dimethylcyclohexanone (4.0 g, 0.032 mol) and hydroxylamine hydrochloride (2.9 g, 0.041 mol) in ethanol (20 mL) was added an aqueous solution (25 mL) of sodium carbonate (4.3 g, 0.041 mol). Added dropwise. The mixture was heated at reflux for 3 hours. The mixture was concentrated in vacuo to remove the ethanol and the aqueous residue was extracted with ethyl acetate. The organic layer was dried (MgSO ₄ ), filtered and concentrated in vacuo to give 3,3-dimethylcyclohexanone oxime as a yellow oil. This material was used without further purification.

Step 2 : (3,3-Dimethylcyclohexyl) amine hydrochloride

A mixture of Raney nickel in ethanol (100 mL) in 3,3-dimethylcyclohexanone oxime (4.41 g, 0.031 mol) and water (1.0 g) was placed in a Parr hydrogenator. After 11 days, the reaction mixture was filtered through celite. To the filtrate was added 1.0N HCl in ethyl ether (50 mL) and the mixture was concentrated in vacuo. The residue was triturated with ethyl ether, filtered, washed with ethyl ether and dried to give (3,3-dimethylcyclohexyl) amine hydrochloride as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (s, 3 H); 0.90 (s, 3 H); 0.97-1.16 (m, 3 H); 1.29 (br d, 1 H); 1.34-1.46 (m, 1H); 1.53-1.63 (m, 2H); 1.90 (br d, 1H); 3.05 (m, 1H); 7.99 (br s, 3H).

[(1S) -3,3-dimethylcyclohexyl] amine hydrochloride and [(1R) -3,3-dimethylcyclohexyl] amine hydrochloride
Step 1 : Phenylmethyl = (3,3-dimethylcyclohexyl) carbamate

To a solution of (3,3-dimethylcyclohexyl) amine hydrochloride (10.0 g, 0.06 mol) and N, N-diisopropylethylamine (15.8 g, 0.12 mol) in acetonitrile (125 mL) cooled in an ice bath, acetonitrile (25 mL A solution of benzyl chloroformate (11.4 g, 0.067 mol) in) was added dropwise. The mixture was stirred and allowed to reach ambient temperature overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 5% aqueous citric acid. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The mixture was filtered, silica gel was added to the residue and the mixture was concentrated in vacuo. The residue was purified by column chromatography using dichloromethane / hexane (4: 1) as eluent to give 11.2 g (70%) of phenylmethyl = (3,3-dimethylcyclohexyl) carbamate as a colorless oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (s, 6H); 0.92-1.02 (m, 3 H); 1.25 (d, 1 H); 1.36-1.52 (m, 3 H); 1.76 (br d, 1 H); 3.36-3.44 (m, 1H); 4.96 (s, 2H); 7.10 (d, 1H); 7.27-7.36 (m, 5H).

Step 2 : Phenylmethyl = [(1S) -3,3-dimethylcyclohexyl] carbamate and phenylmethyl = [(1R) -3,3-dimethylcyclohexyl] carbamate Phenylmethyl = (3,3-dimethylcyclohexyl) carbamate (11.2 g) was separated on a Chiralpak AS column (30 mm) by supercritical liquid chromatography (SFC). The flow rates were 75 gr / min CO ₂ and 4 mL / min ethanol. The pressure was 140 bar and the temperature was 40 ^° C. Enantiomers eluting at 4.41 minutes were combined and concentrated in vacuo to give 3.98 g of a colorless oil. Analytical SFC showed that this enantiomer was> 99% pure. Ab Initio vibrational circular dichroism confirmed that this was the S-enantiomer. [α] _D = -17.2 ° (c = 0.01, methanol), optical rotation was obtained at 25 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (s, 6H); 0.93-1.01 (m, 3 H); 1.25 (d, 1 H); 1.33-1.52 (m, 3 H); 1.75 (br d, 1 H); 3.35-3.44 (m, 1H); 4.96 (s, 2H); 7.08 (d, 1H); 7.25-7.35 (m, 5H). (M + 1) 262, 2.8 min (LC / MS method A).

Enantiomers eluting at 5.51 minutes were combined and concentrated in vacuo to give 3.57 g of a colorless oil. Analytical SFC showed that this enantiomer was> 99% pure. Ab Initio vibrational circular dichroism confirmed that this was the R-enantiomer. [α] _D = + 16.3 ° (c = 0.011, MeOH), optical rotation was obtained at 25 ° C. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (s, 6H); 0.92-1.01 (m, 3 H); 1.25 (d, 1 H); 1.33-1.52 (m, 3 H); 1.75 (br d, 1 H); 3.36-3.44 (m, 1H); 4.96 (s, 2H); 7.08 (d, 1H); 7.26-7.35 (m, 5H), (M + 1) 262, 2.86 min (LC / MS method B).

Step 3 : [(1S) -3,3-Dimethylcyclohexyl] amine hydrochloride

Phenylmethyl = [(1S) -3,3-dimethylcyclohexyl] carbamate (1.0 g, 0.004 mol) and 10% Pd / C (0.15 g) in 10 mL of MeOH were placed under a hydrogen balloon for 24 hours. The catalyst was removed by filtration through Celite®. To the filtrate was added 1N HCl in ethyl ether (2.5 mL) and the mixture was left at room temperature overnight. The mixture was concentrated in vacuo. The residue was triturated with ethyl ether. The resulting solid was filtered, washed with ethyl ether and dried in vacuo to give 0.41 g (66%) of [(1S) -3,3-dimethylcyclohexyl] amine hydrochloride as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.89 (s, 3H); 0.93 (s, 3H); 1.00-1.17 (m, 3H); 1.33 (br d, 1H); 1.38-1.49 ( br q, 1H); 1.58-1.63 (m, 2H); 1.92 (br d, 1H); 3.06-3.14 (m, 1H); 7.86 (s, 3H).

Step 4 : [(1R) -3,3-dimethylcyclohexyl] amine hydrochloride

Phenylmethyl = [(1R) -3,3-dimethylcyclohexyl] carbamate (1.0 g, 0.004 mol) and 10% Pd / C (0.15 g) in 10 mL of MeOH were placed under a H ₂ balloon for 20 hours. The catalyst was removed by filtration through Celite®. To the filtrate was added 1N HCl in ethyl ether (3.0 mL) and the mixture was concentrated in vacuo. The residue was triturated with ethyl ether containing 1N ethereal hydrogen chloride (0.5 mL). The resulting solid was filtered, washed with ethyl ether and dried in vacuo to give 0.56 g (90%) of [(1R) -3,3-dimethylcyclohexyl] amine hydrochloride as a white solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.85 (s, 3H); 0.90 (s, 3H); 0.96-1.14 (m, 3H); 1.29 (br d, 1H); 1.35-1.45 ( br q, 1H); 1.53-1.61 (m, 2H); 1.89 (br d, 1H); 3.02-3.09 (m, 1H); 7.88 (s, 3H).

Test method
LC-MS Method A (Standard Electrospray Method) : Use a mass spectrometer to confirm peak identity for 100-1000 m / z electrospray +/- ionization scan and 220-400 nm DAD. Phenomenex Luna column 4.6mm / 2cm, particle size 3μm, ambient temperature. At a solvent flow rate of 2 ml / min. The gradient starts with 10% MeOH and reaches 100% MeOH in 3 minutes linearly and is kept at 100% MeOH for 1 minute, giving a total chromatogram time of 4 minutes. 2 μl sample injection. The mobile aqueous phase contains 0.1% v / v formic acid and MeOH contains 0.075% v / v formic acid.

LC-MS Method B (Standard APCI Method) : Confirm peak identity using a mass spectrometer for 100-1000 m / z APCI +/− ionization scan and 220-400 nm DAD. Phenomenex Luna column 4.6mm / 2cm, particle size 3μm, ambient temperature. At a solvent flow rate of 2 ml / min. The gradient starts with 10% MeOH and reaches 100% MeOH in 3 minutes linearly and is kept at 100% MeOH for 1 minute, giving a total chromatogram time of 4 minutes. 2 μl sample injection. The mobile aqueous phase contains 0.1% v / v formic acid and MeOH contains 0.075% v / v formic acid.

LC-MS Method C (Polar Electrospray Method) : Confirm peak identity using a mass spectrometer for 100-1000 m / z electrospray +/- ionization scan and for 220-400 nm DAD. Phenomenex Luna column 4.6mm / 2cm, particle size 3μm, ambient temperature. At a solvent flow rate of 2 ml / min. The gradient starts at 2% MeOH and reaches 26% MeOH in 1 minute linearly. The gradient is then linearly changed from 26% to 100% from time 1 minute to time 3 minutes, held at 100% MeOH for 1 minute, and the total chromatogram time is 4 minutes. 2 μl sample injection. The mobile aqueous phase contains 0.1% v / v formic acid and MeOH contains 0.075% v / v formic acid.

LC-MS method D (basic electrospray method) : Confirm peak identity using a mass spectrometer for 100-1000 m / z electrospray +/- ionization scan and for 220-400 nm DAD. Phenomenex Luna column 4.6mm / 2cm, particle size 3μm, ambient temperature. At a solvent flow rate of 2 ml / min. The gradient starts with 10% MeOH and reaches 100% MeOH in 3 minutes linearly and is kept at 100% MeOH for 1 minute, giving a total chromatogram time of 4 minutes. 2 μl sample injection. The mobile aqueous phase contains 0.1% v / v ammonium hydroxide and is at pH 10, and MeOH does not contain ammonium hydroxide.

LC-MS Method E (Polar APCI Method) : Confirm peak identity using a mass spectrometer for 100-1000 m / z APCI +/− ionization scan and 220-400 nm DAD. Phenomenex Luna column 4.6mm / 2cm, particle size 3μm, ambient temperature. At a solvent flow rate of 2 ml / min. The gradient starts at 2% MeOH and reaches 26% MeOH in 1 minute linearly. The gradient is then linearly changed from 26% to 100% from time 1 minute to time 3 minutes, held at 100% MeOH for 1 minute, and the total chromatogram time is 4 minutes. 2 μl sample injection. The mobile aqueous phase contains 0.1% v / v formic acid and MeOH contains 0.075% v / v formic acid.

LC-MS Method F (Standard Electrospray Rapid Mass Spectrometry) : 100-800 m / z electrospray + ionization scan and 220-400 nm DAD sum. Waters Acquity UPLC column 2.1mm / 5cm, particle size 1.7μm, temperature 40 ℃. At a solvent flow rate of 1 ml / min. The gradient starts at 6% ACN and reaches 70% ACN linearly at 0.57 minutes; then the gradient reaches 99% ACN linearly, reaches 0.57 to 1.06 minutes, holds 99% ACN until 1.5 minutes, The total chromatogram time is 1.5 minutes. 1.5 μl sample injection. The mobile aqueous phase contains 0.1% v / v formic acid and ACN contains traces v / v formic acid.

The compounds of the present invention have a functional antagonist activity of pIC ₅₀ > 5 (10 micromolar) at at least one opioid receptor.

Remark 1 : In one preparation method of Example Nos. 1 and 2, the oxidation in Step 4 of General Method 1 was performed by swern oxidation as follows.

DMSO (dimethyl sulfoxide) (0.415 mL, 5.37 mmol) was added dropwise to a solution of oxalyl chloride (0.293 mL, 335 mmol) in 25 mL of CH ₂ Cl ₂ at −78 ° C. and stirred for 30 minutes. A solution of [4- (1H-benzimidazol-5-yloxy) phenyl] methanol (0.644 g, 2.69 mmol) in 20 mL CH ₂ Cl ₂ and 10 mL DMSO is added to the reaction and at −78 ° C. for 30 min. Stir. Triethylamine (1.5 mL, 10.7 mmol) was added and the reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with water and extracted with CH ₂ Cl ₂ , dried over MgSO ₄ and concentrated. The crude residue was retreated under reaction conditions with 2 volumes of each reagent and then stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with CH ₂ Cl ₂ , dried over MgSO ₄ and concentrated. Crude 4- (1H-benzimidazol-5-yloxy) benzaldehyde was used in the next step without further purification.

Remark 2 : For Example Nos. 7 and 8, the reductive amination of General Method 1, Step 5 was performed with sodium triacetoxyborohydride as follows and then treated with NaCNBH ₃ .

Representative Example : Preparation of N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} cycloheptanamine = bis (trifluoroacetate) (Example No. 8)

4- (1H-Benzimidazol-5-yloxy) benzaldehyde (200 mg, 0.839 mmol), cycloheptylamine (0.214 mL, 1.68 mmol) and sodium triacetoxyborohydride (534 mg, 2.52 mmol) in 10 mL 1,2 dichloromethane Shake for almost 18 hours. Two drops of acetic acid and excess NaCNBH ₃ were added and the reaction was stirred overnight at room temperature. The reaction was concentrated and the residue was dissolved in ethyl acetate and 1N NaOH. The organic layer was added to a Varian Chem Elute® 1001 column, which was rinsed with 4-6 ml of ethyl acetate (gravity filtration) to elute the crude product. The eluate was concentrated. The residue was dissolved in 1.5-2 ml methanol and approximately 150 μl trifluoroacetic acid and purified using preparative HPLC to give N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} cycloheptane Amine bis (trifluoroacetate) (Example No. 8) was obtained.

Remark 3 : N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2- (4-fluorophenyl) ethanamine dihydrochloride (Example No. 16) was prepared using general method 4. Although prepared, it was not pure. The compound was dissolved in ethyl acetate and stirred with di-tert-butyl dicarbonate (1 eq) and saturated NaHCO ₃ for 30 minutes. The organic layer was separated, washed with saturated NaHCO ₃ and concentrated. The residue was purified by preparative HPLC. The pure fractions were diluted with ethyl acetate, washed with 1N NaOH, dried over MgSO ₄ and concentrated. The residue was dissolved in 25 mL of CH ₂ Cl ₂ and stirred with dioxane containing 2 mL of 4N HCl for approximately 18 hours and then concentrated. The residue was dissolved in methanol and concentrated to give N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2- (4-fluorophenyl) ethanamine dihydrochloride (Example No. 16). Was obtained as a white solid.

Note 4 : Method 1 Step 5 reductive amination consists of 4- (1H-benzimidazol-5-yloxy) benzaldehyde (60 mg, 0.25 mmol), trans-decahydroisoquinoline (53 mg, 0.38 mmol), and excess Argonaut MP. Triacetoxyborohydride resin was performed by shaking in THF. Since the reaction was not complete, NaCNBH ₃ (100 mg) was added. The reaction mixture was filtered and the filtrate was diluted with water, basified with 10N NaOH, extracted twice with ethyl acetate and concentrated. The crude product was purified by preparative HPLC to give Example No. 24.

Note 5 : When prepared by General Method 3, Example No. 73 was purified by column chromatography using a silica column functionalized with Isco amine (0-10% methanol / CH ₂ Cl ₂ gradient). This material was then purified by preparative HPLC to give pure N-{[4- (1H-benzimidazol-5-yloxy) -2-chlorophenyl] methyl} -2,3-dihydro-1H-inden-2-amine = Bis (trifluoroacetate) (Example No. 73) was obtained.

Note 6 : For Example Nos. 73 and 74, the product of General Method 6, Step 4 required an additional step (below) to remove the acetal protecting group.

5-{[3-Chloro-4- (1,3-dioxolan-2-yl) phenyl] oxy} -1H-benzimidazole (1.41 g) was dissolved in approximately 15 mL acetone and 25 mg p- over 3 days. Heated to reflux with tosylic acid. An additional 50 mg of p-tosylic acid was added and the reaction was heated at 80 ° C. for an additional 6 hours. The reaction was cooled to room temperature, diluted with water and ethyl acetate, basified with 10N NaOH and extracted with ethyl acetate. The organic layer was washed with brine and 1N NaOH, dried over MgSO ₄ and concentrated. The residue was dissolved in raw trifluoroacetic acid and stirred. The reaction was concentrated and purified by silica gel column chromatography (0-10% gradient methanolic 2NNH ₃ / CH ₂ Cl ₂ ). The fractions were concentrated and the residue was purified by preparative HPLC to give 4- (1H-benzimidazol-5-yloxy) -2-chlorobenzaldehyde, which was used finally to give Example No. 73 and 74 was prepared.

Note 7 : When prepared by General Method 5, Example No. 87 was purified by preparative HPLC using a Luna C18 column and a 10-50% acetonitrile gradient in water. The solvent contained 0.1% formic acid.

Claims (19)

Formula 1:

[Wherein R ¹ is hydrogen, C _1-12 alkyl, C _3-10 cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl, provided that the carbon atom bound to nitrogen is not aromatic or carbonyl. Selected from the group consisting of _:, heteroarylalkyl, cycloalkenyl, C _2-12 fluoroalkyl, C _3-10 alkoxy, and heteroalkyl;
R ² is C _3-12 alkyl, C _3-10 cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl, heteroarylalkyl, cyclo, provided that the carbon atom bonded to the nitrogen is not aromatic or carbonyl. Selected from the group consisting of alkenyl, C _3-12 fluoroalkyl, C _3-10 alkoxy, and heteroalkyl;
R ¹ and R ² may be optionally joined to form a ring;
A is attached in the meta or para position to the diaryl ether linker and is C _1-3 alkylene;
R ³ and R ⁴ are each independently of the group consisting of —H, —F, —Cl, —Br, —OH, —OC _1-3 alkyl, —C _1-3 fluoroalkyl and —C _1-3 alkyl. Selected;
X, Y, and Z are each independently -N, -NH, -CH, -O, -S, -NR ⁵ , and -CR ⁶ (where R ⁵ and R ⁶ are each independently C ₁ Selected from the group consisting of _-6 alkyl or fluoroalkyl];
And pharmaceutically acceptable salts, solvates, or physiologically functional derivatives thereof.   The compound of claim 1, wherein A is methylene bonded in the para position to the diaryl ether linker. R ¹ is hydrogen; R ² is selected from the group consisting of arylmethyl, arylethyl, C _4-10 alkyl, cycloalkenyl, cycloalkyl, heteroalkyl, heteroarylmethyl, heteroarylethyl, heterocyclylmethyl, and heterocyclylethyl The compound according to claim 2, wherein R ³ and R ⁴ are each independently selected from the group consisting of H, methyl, and F.   4. A compound according to claim 3, wherein either X or Z is -NH and the other is -CH or -N; and Y is -CH or -N. The compound of formula 1 is
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -3-methyl-1-butanamine = trifluoroacetate;
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -4,4-dimethylcyclohexaneamine = trifluoroacetate;
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2- (3-fluorophenyl) ethanamine = trifluoroacetate;
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2- (2-thienyl) ethanamine = trifluoroacetate;
{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} (cyclohexylmethyl) amine = trifluoroacetate;
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} cycloheptanamine = trifluoroacetate;
N-{[4- (1H-benzimidazol-5-yloxy) phenyl] methyl} -2- (tetrahydro-2H-pyran-4-yl) ethanamine = trifluoroacetate;
(Cyclohexylmethyl) {[4- (1H-indazol-5-yloxy) phenyl] methyl} amine hydrochloride; and
2. The compound of claim 1 selected from the group consisting of [2- (3-fluorophenyl) ethyl] {[4- (1H-indazol-5-yloxy) phenyl] methyl} amine hydrochloride.   A pharmaceutical composition comprising (i) a compound of formula 1, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, and (ii) at least one carrier.   A method for treating a symptom selected from the group consisting of obesity, diabetes, hypertension, depression, anxiety, drug addiction, and substance addiction, comprising: (i) a compound of formula 1, a pharmaceutically acceptable salt thereof, a solvent A method as described above, comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition comprising a sum, or a physiologically functional derivative and (ii) at least one carrier.   8. A compound according to claim 7, wherein the mammal is a human.   A method of treating a condition selected from the group consisting of obesity, diabetes, hypertension, depression, anxiety, drug addiction, and substance addiction, comprising a compound of formula 1, a pharmaceutically acceptable salt, solvate thereof, Or said method comprising administering to the mammal a therapeutically effective amount of a physiologically functional derivative.   10. A compound according to claim 9, wherein the mammal is a human.   2. A compound according to claim 1, a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof, for use as an active therapeutic substance.   2. The compound of claim 1, a pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof for use as an antagonist or inverse agonist of one or more opioid receptors.   The compound of claim 1, a pharmaceutically acceptable salt thereof, a solvent for use in the treatment of a symptom selected from the group consisting of obesity, diabetes, hypertension, depression, anxiety, drug addiction, and substance addiction Japanese or physiologically functional derivatives.   14. A compound according to claim 13, wherein the treatment is treatment of obesity symptoms.   2. The compound of claim 1, in the manufacture of a medicament for use in the treatment of a condition selected from the group consisting of obesity, diabetes, hypertension, depression, anxiety, drug addiction, and substance addiction, its pharmaceutically acceptable Use of salts, solvates, or physiologically functional derivatives.   16. Use according to claim 15, wherein the treatment is treatment of symptoms of obesity.   2. In combination with at least one other chemical species selected from the group consisting of at least one drug or drug to treat obesity, diabetes, hypertension, drug addiction, substance addiction, and arteriosclerosis. A compound, pharmaceutically acceptable salt, solvate, or physiologically functional derivative thereof. Human ciliary affinity factor, CB-1 antagonist or inverse agonist, neurotransmitter reuptake inhibitor, lipase inhibitor, MC4R agonist, 5-HT2c agonist, ghrelin receptor antagonist, CCK-A receptor agonist, NPYY1 antagonist, PYY ³ _-36 and in combination with at least one other species selected from the group consisting of PPAR activator compound of claim 17.   A process for preparing a pharmaceutical composition comprising mixing a compound of formula 1 or a salt, solvate, or physiologically functional derivative thereof with one or more pharmaceutical excipients.